LARGE-SCALE CENTERS FOR THE PROTEIN STRUCTURE INITIATIVE
 
RELEASE DATE:  April 1, 2004
 
RFA Number: RFA-GM-05-001

EXPIRATION DATE:  October 16, 2004

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)   

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of General Medical Sciences (NIGMS) 
 (http://www.nigms.nih.gov) 

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.859 
 
LETTER OF INTENT RECEIPT DATE:  September 10, 2004
APPLICATION RECEIPT DATE:  October 15, 2004   
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o  Purpose of this RFA
o  Research Objectives
o  Mechanism of Support
o  Funds Available
o  Eligible Institutions
o  Individuals Eligible to Become Principal Investigators
o  Special Requirements
o  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
o  Supplementary Instructions
o  Peer Review Process
o  Review Criteria
o  Additional Review Considerations
o  Receipt and Review Schedule
o  Award Criteria
o  Required Federal Citations

PURPOSE OF THIS RFA 

The National Institute of General Medical Sciences (NIGMS) encourages 
applications for cooperative agreements to support large-scale 
structural genomics research centers for the determination of unique 
protein structures.  These centers will form one component of the 
Protein Structure Initiative (PSI) Research Network, the integrated 
second, or production, phase of the PSI (PSI-2).  Each large-scale 
center must perform all tasks of structural genomics in a high-
throughput operation to produce a large number of unique protein 
structures to meet the PSI-2 goals for structural coverage of sequenced 
genes.  Each large-scale center must also develop technologies and 
methodologies that will make the production and structural 
determination of proteins less expensive, more efficient, and more 
likely to be successful. 

RESEARCH OBJECTIVES

A. Background

With the completion of the sequencing of the genomes of human and other 
organisms, attention has focused on the functional characterization of 
large sets of proteins.  The availability of sequence data, 
computational analyses of protein sequence families, technological 
developments in x-ray crystallography and nuclear magnetic resonance 
(NMR) spectroscopy, and the growing impact of structural biology on 
biomedical research has led to an international effort to determine 
protein structures on a large scale and to the emerging field of 
structural genomics.  The NIGMS played a major role in the early 
planning for this field and in 1999 organized a national program, the 
Protein Structure Initiative (PSI).

The long-range goal of the PSI is to make the three-dimensional atomic 
level structures of most proteins easily obtainable from knowledge of 
their corresponding DNA sequences.  The PSI plans to accomplish this 
goal by the creation and distribution of a large collection of protein 
structures. Structural studies by X-ray crystallography and NMR in a 
high throughput mode of operation will achieve a systematic sampling of 
major protein families.  These experimentally determined structures 
will be used as templates for computational modeling of related protein 
homologs to produce structural coverage of a majority of sequenced 
genes.  As it grows, the PSI collection of structures is expected to 
have a significant impact on biological and medical research, in a way 
similar to the human genome project.  These structures will help 
researchers discover the functions of proteins, design better 
experiments, and study key biomedical problems such as protein folding, 
structure prediction, and the organization of protein families and 
folds.  In addition, the results of these studies will be useful for 
faster identification of promising new structure-based medicines, 
better therapeutics for treating both genetic and infectious diseases, 
and development of technology and methodology for protein production 
and crystallography.  For more details about the PSI's goals, 
organization, and benefits, see the PSI mission statement at: 
http://www.nigms.nih.gov/psi/mission.html.  Additional information 
about the PSI can be found under the links listed below. 
 
Prior to initiating the PSI, the NIGMS organized three workshops 
composed of experts from the scientific community to examine 
feasibility, constituent tasks, goals, planning, and target selection 
for this project.  There was general agreement on technical feasibility 
due to advances in the development of high-throughput expression 
systems, protein purification, sample preparation, and structure 
determination by X-ray crystallography and NMR.  It was agreed that all 
tasks could be organized on the large scale required.  A summary of 
these meetings can be found on the NIGMS web site at: 
http://www.nigms.nih.gov/psi/.  Following these workshops and 
discussions by the National Advisory General Medical Sciences Council 
(NIGMS Council), the PSI was initiated.    

The pilot phase of the PSI began in 2000 with a 5-year program for the 
development of research centers.  The principal goal of the pilot phase 
is the development of a structural genomics pipeline for the 
determination of unique protein structures in a high-throughput 
operation.  This program was designed to test all facets and strategies 
for the subsequent production phase of the PSI.  Protein targets are 
chosen as representatives of sequence families and thus provide broad 
structural coverage of sequenced gene products.  Most of the nine pilot 
centers use the 30% sequence identity rule (less than 30% of the 
sequence is identical to the sequence of a known structure) and/or 
profile methods to identify targets for unique protein structures.  
Each pilot center also includes other criteria relevant to feasibility 
and its own scientific mission:  biological function, medical 
relevance, etc.  Over 70% of the structures produced by the PSI pilot 
centers are unique by the 30% sequence identity rule.  Duplication of 
effort is avoided by the public listing of all protein targets (See 
Special requirement B.1).  Major investments in technology and 
methodology development at the nine PSI research centers are making 
each step of experimental structure determination more efficient, less 
expensive, and more likely to succeed.  More information on the nine 
PSI pilot centers and the technological developments can be found at 
the PSI website: http://www.nigms.nih.gov/psi/.  In addition to the PSI 
pilot research center program, the Institute has supported the 
development of methodology and technology underpinning the structural 
genomics through two research programs for individual investigators, 
program projects, and small business grants (PA-99-116 and PA-99-117, 
http://grants.nih.gov/grants/guide/pa-files/PA-99-116.html and 
http://grants.nih.gov/grants/guide/pa-files/PA-99-117.html).  The 
NIGMS PSI program has also sponsored and/or organized numerous 
workshops for the pilot centers to address technical bottlenecks to 
high-throughput operation.  These workshops covered the following:  
general structural genomics bottlenecks, x-ray diffraction, NMR, 
protein production, data deposition, protein production and 
crystallization, data management, homology modeling, and target 
selection.  Researchers in the pilot projects have used a diversity of 
approaches to overcome these problems, and progress has been reported 
in the workshops, scientific meetings, and various publications. 
Reports of these workshops are available at the PSI website at: 
http://www.nigms.nih.gov/psi/meetings.html. 

B. Programmatic Summary

Analyses of the results of the pilot research centers by the NIGMS 
staff, PSI Advisory Committee (See Special requirement A.8), and the 
NIGMS Council, have led to the following summary:
1.  Structural genomics pipelines can be constructed and scaled-up.  
This process takes considerable investment in robotic instruments, 
laboratory and data management systems, staff training, etc.  Scaling- 
up takes time and care but can be accomplished. 
2.  High-throughput operation works for many proteins and has led to 
many successful determinations of protein structures.  The development 
and incorporation of robotic instruments, standard protocols, and 
laboratory/data management systems have made notable impact on cost, 
efficiency, success, and time in the passage from DNA sequence to 
structure.  Thus far, most of the proteins that have been solved are 
the  low-hanging fruit  -  easy to express and purify.  
3.  The structural genomics approach of choosing multiple targets is 
successful.  Although the automated approaches are effective, the 
chance of successfully determining a structure for a given target is 
still not high.  However, with multiple targets available for most 
protein families, the likelihood of obtaining the structure of one 
family representative is significantly increased.
4.  Bottlenecks remain for some proteins, such as membrane proteins, 
proteins from human and other higher eukaryotes, and small protein 
complexes.  These challenging proteins are significantly more difficult 
to produce and crystallize.  
5.  A coordinated, 5-year target selection policy must be developed.  
The pilot phase approach has worked well, with few duplicate structures 
produced and most of the structures being unique family representatives 
at the time of deposition.  Additional coordination on target selection 
is called for in PSI-2 since a higher level of protein structure output 
is expected.
6.  Homology modeling methods need improvement.  Steady improvement has 
been noted in the methods for comparative homology modeling.  However, 
major improvement is needed to improve the accuracy of the models and 
decrease the number of experimental structures that need to be 
determined.
7.  The impact of the PSI to the broad scientific community should be 
increased.  Benefits from the PSI structures and technologies are 
growing, but more activities are needed to utilize these results fully.

C. Objectives
 
The purpose of this RFA is to announce support for large-scale centers 
for the high-throughput production of unique protein structures by X-
ray crystallography and NMR methods.  These research centers will be 
one component of the PSI Research Network in structural genomics.  

PSI Research Network: The production phase, PSI-2, will consist of an 
interacting network with four components.  
o  In the first component, large-scale research centers will perform 
every step of the structural genomics process starting with DNA 
sequences and leading to the high throughput determination of a large 
collection of unique protein structures.  These large-scale PSI 
research centers are the subject of this announcement (GM-05-001) and 
are described in detail below.  
o  The second component of the PSI Network will focus on the 
development of new methods, technology, approaches, and ideas for 
protein production and structure determinations for especially 
challenging proteins, including membrane proteins, small protein 
complexes, and proteins from human and other higher eukaryotes.  These 
specialized centers will be supported by NIGMS and the National Center 
for Research Resources (NCRR) and are described in a separate 
announcement (GM-05-002).  
o  The third component of the PSI Network will consist of specialized 
centers that determine protein structures from microorganisms, tissues, 
or organ systems related to specific diseases.  This third component of 
the PSI Network is being considered as an activity of the NIH 
Structural Biology Roadmap initiative.  
o  The fourth component of the PSI Network is the development and 
operation of the PSI Network Knowledge Base.  This component will serve 
as an interface, linking data from the PSI research centers with the 
Protein Data Bank (PDB) and other major databases related to the PSI.  
This resource will be a central information hub for the PSI Research 
Network.  It will analyze and organize the results from a structural 
genomics perspective.  The NIGMS staff is currently developing a 
mechanism for supporting this component. 
o  Other related research projects can be added to the PSI Network if 
determined appropriate by the Director of the PSI Network.

Features of large-scale centers:  The large-scale research centers will 
operate high-throughput structural genomics pipelines for the protein 
production and structure determination that is necessary for this 
production phase.  The large-scale centers should contain all of the 
constituent tasks of structural genomics (See section below) and should 
demonstrate the ability to accomplish these in a high-throughput 
operation.  Effective plans for management and administration of the 
research centers are crucial.  Attention should be paid to costs, 
success rates, and efficiency.  Rapid release of data into the public 
databases is required.  Continuing development of technologies and 
methodologies is also required.  Target selection will focus on 
representatives of large protein families to maximize the number of 
structures that can be modeled from this set of experimental 
structures, as described below.  Each of these large-scale research 
centers must solve a large number of unique protein structures each 
year.  This number and appropriate milestones for each center will be 
determined by the NIGMS staff, following discussions by the Steering 
Committee and members of the PSI Advisory Committee.  For the easier 
targets (the "low-hanging fruit") this number is expected to be about 
200 unique structures per year per center.  This goal seems achievable 
based on the progress demonstrated in the pilot phase in developing 
protocols and automation for high-throughput operation for many protein 
targets. These large-scale centers will also serve as centralized 
facilities capable of providing structural information quickly in 
response to critical biological and medical problems.  

Constituent task of the large-scale centers: 
1. Family classification and target selection:  There are several 
schemes of protein sequence clustering for parsing proteomes into 
protein families and for choosing protein targets for structural 
genomics projects.  Target selection will continue to emphasize the 
selection of proteins as representatives of sequence families to 
rationally search for unique protein structures.  In PSI-2 targets will 
be selected to maximize structural coverage of most sequenced genes, as 
described below.  
2. Generation of protein for biophysical analyses:  The center 
applicants will be expected to demonstrate the capability for high 
throughput cloning, expression, and purification systems to produce 
large quantities of target proteins in a form suitable for biophysical 
studies.  Emphasis should be on rates of success, efficiency, and cost 
savings.
3. Sample preparation for structural studies:  This crucial 
experimental task has seen significant progress, with significant 
improvement in the ability of structural biologists to crystallize 
proteins and label protein samples for NMR studies.  Applicants must 
demonstrate their experience and plans for the preparation of samples 
for structure determinations in a high- throughput mode.  
4. Challenging protein targets:  Some classes of proteins are still not 
amenable to high-throughput operations.  These include membrane 
proteins, protein complexes, and proteins from human and other higher 
eukaryotes.  The PSI-2 large-scale centers are expected to include 
challenging proteins in their target selection plans and to plan for an 
innovative subproject focused on the production and structural 
determination of one or more classes of these proteins. 
5. Structure determination:  High-resolution structure determination is 
becoming straightforward for many protein samples. Crystallography has 
benefited from the almost universal use of synchrotron beamlines 
coupled with new detectors, cryocrystallographic techniques, multiple-
wavelength anomalous diffraction techniques, and advanced computational 
systems for rapid data collection, processing, and model building.  New 
NMR methods and higher field instruments have increased the size of 
proteins that can be solved by this technique.  The structure 
determination component should be the nucleus of a structural genomics 
research center.  Applicants for the PSI-2 large-scale research centers 
must have considerable expertise and resources in either or both of 
these techniques and are expected to demonstrate their access to state-
of-the-art synchrotron and/or NMR facilities.  The NIGMS is currently 
developing additional beamlines at several synchrotron facilities and 
will likely be able to make additional beamtime available to general 
users and research centers funded by this RFA within the next few 
years.  However, the PSI-2 research centers are expected to present 
their own plans for data collection and structure determinations.
6. Analyses and dissemination of results:  The research centers will be 
expected to analyze their structures by computational techniques for 
biomedical significance, including functional characterization and 
evolutionary and structural relationships.  Since the goal of this 
initiative is to add to the body of knowledge of protein structure, 
timely release and dissemination of results are crucial.  These results 
include information on strategies for target selections, status of 
these proteins in the structural genomics pipeline, technological and 
methodology findings, high throughput approaches, efficiency, and cost 
analyses.  The research centers are required to have plans for timely 
deposition of coordinates and related data into the Protein Data Bank 
(PDB) and other relevant public databases, consistent with NIH policies 
and PSI programmatic goals. (See Special requirements B.1)
7. Management and administration:  With several components that are 
interdependent, management and administration of the center are 
crucial.  In addition to the usual administrative requirements, the 
leadership of each research center must direct the research and make a 
wide range of decisions about subcontracts, equipment purchases, 
staffing, standard protocols, pipeline priorities and protocols, etc.  
Special PSI requirements, such as cooperative agreement commitments, 
annual reports, attendance at PSI meetings, participation of minority 
scientists and students, outreach to the scientific community, research 
training, intellectual property, participation in the PSI Network, 
etc., must be incorporated by the applicant into the organization of 
each research center. 

Target selection for PSI-2:  Since its inception in 1999, the general 
principle for target selection for the Protein Structure Initiative has 
focused on representatives of protein sequence families for which there 
are no known structures.  This approach leads to the determination of 
unique, non-redundant protein structures and is the policy followed in 
the PSI pilot phase.  Although the target selection policy for PSI-2 
begins with this general principle, a more specific policy is required 
for this subsequent and more focused phase.  The NIGMS staff has 
determined that the best specific strategy for target selection for the 
PSI Network and PSI-2 is to concentrate on large protein families in 
order to provide the broadest possible structural coverage of sequenced 
genes.  A secondary goal aims directly at biomedical impact with 
projects focusing on specific pathways, organisms, systems, etc.  

These conclusions were reached through a lengthy planning process.  
Prior to the PSI pilot RFA, the NIGMS held a workshop on target 
selection.  More recently, in November 2003, another workshop focused 
on this issue 
(http://www.nigms.nih.gov/psi/meetings/target_selection.html ) as well 
as a meeting with the PSI Advisory Committee in December 2003 
(http://www.nigms.nih.gov/psi/meetings/psi-advisory-centers.html ).  At 
these meetings, most participants agreed on the strategy for structural 
coverage of sequenced genes by focusing on structural determination of 
large protein sequence families.  Experts from genomic and other 
biomedical fields discussed the appropriate balance of genomic coverage 
and biomedical impact.  A crucial issue in these discussions was the 
appropriate level of the detail, or granularity, of structural coverage 
of sequenced genes.  At coarse granularity, sequence homology 
comparisons are carried out by PSI-BLAST or other profile-based methods 
to produce protein families with distant evolutionary links.  This 
parsing leads to fewer families, each with more members.  As a result, 
fewer experimental structures will be needed for structural coverage of 
sequenced genes, and the structural models generated will be moderately 
accurate for distant homologs in the same family.  On the other hand, 
structural coverage at fine granularity, chosen, for example, as 30% 
sequence identity, would lead to a larger number of sequence families, 
each with fewer members.  At this fine granularity, more experimental 
structures will be required, and the computational models generated 
thereafter would in general be more accurate and suitable for studying 
biological function.  In this workshop and in discussions with the PSI 
Advisory Committee members, the NIGMS Council, and members of the 
scientific community, there was general agreement among the 
participants of the workshop and meetings that 1) 4-5,000 experimental 
structures representing large sequence families would provide 
structural coverage at coarse granularity of sequenced genes, 2) this 
collection of structures would be a valuable resource for the 
biomedical community, 3) this project should be the primary goal for 
PSI-2, and 4) this project could be achieved in the 5-year term of PSI-2.  

Most of the scientists attending these meetings and workshops agreed on 
another mission for PSI-2: the focus on specific biomedical research 
problems from a structural genomics approach.  The determination of a 
collection of unique, non-redundant protein structures for specific 
pathways, organisms, and/or groups of proteins was seen to have high 
scientific value. For this secondary goal, it was suggested that each 
center plan and carry out a research project with a significant 
biomedical theme, choosing appropriate protein targets for structural 
coverage at either fine or coarse granularity.  The structural genomics 
pipeline would be utilized for production and structural determination 
of the proteins chosen to address this scientific problem.  In 
addition, other protein targets could be nominated by members of the 
scientific community as part of this biomedical theme component of PSI-2.  

Target selection goals for the large-scale centers:  Following these 
meetings and workshops and other discussions with members of the 
scientific community, the NIGMS staff has determined that the target 
selection policy for PSI-2 should reflect a balance between structural 
coverage of sequenced genes and the exploration of biomedically 
important pathways and systems, as described in the previous 
paragraph.  As the facilities that will be charged with carrying out 
these goals, each large-scale center must develop plans for the 
following:

Target selection goal #1. Complying with the decisions of the Steering 
Subcommittee on Target Selection for structural coverage of a majority 
of sequenced genes by the determination of representative structures of 
large protein families at coarse granularity (See Special requirement 
A.7).  This part should encompass the majority of the center’s effort.  
Each applicant must identify groups of proteins (e.g., pan-genomic or 
multiple prokaryotes and/or eukaryotes) that the center will consider 
in the selection of targets and explain why they are appropriate for 
high-throughput operation and large-scale output and for meeting the 
structural coverage goals of the PSI Network.  

Target selection goal #2. Carrying out a structural genomics research 
project with a significant biomedical theme.   Each center must propose 
a biomedical research project that leads to a collection of unique, 
non-redundant protein structures and structural coverage at fine or 
coarse granularity of protein families from specific pathways, 
organisms, and/or groups of proteins of high scientific value.  Protein 
targets must be selected by each center for high throughput protein 
production and structure determination to address this scientific 
problem.   The applicant must provide details on goals, plans, and 
impact of the project.  

Target selection goal #3. Complying with the decisions of the 
Subcommittee on Target Selection for structural coverage at fine or 
coarse granularity of proteins that are proposed by the scientific 
community to the PSI Network.  The effort toward this activity should 
be approximately equal to that of the second part.
 
After the initiation of PSI-2, the Steering Committee and the PSI 
Advisory Committee will meet jointly with the NIH staff to determine 
how to carry out target selection for the PSI Network.  Further 
refinement of the target selection criteria by these same groups will 
occur on a regular basis as the PSI-2 project matures.  Each research 
center should have plans for target selection of proteins for 
experimental structural determination to fulfill the PSI objectives as 
stated above.  Each center must participate in all discussions on 
target selection and have plans for completing the work outlined by the 
Steering Committee.

Technology development: Advances in technology and methodology during 
the PSI pilot phase have permitted the establishment of a structural 
genomics pipeline approaching an industrial scale.  In particular, 
average costs per structure have decreased markedly, but further 
reductions to about $50,000 total costs per structure are essential for 
meeting the PSI-2 goals.  Success rates of each component of the 
pipeline have also improved, but are not sufficient.  The numerous 
facets and difficulties of each step of the production and 
determination of unique protein structures require continued technology 
and methodology development during the production phase.  Existing 
equipment, standard protocols, and laboratory/data management systems 
can be scaled up, but further technical breakthroughs and innovation 
are necessary for reaching the long-term goals of the PSI.  In PSI-2, 
the large-scale centers must continue methodology and technology 
development to improve all elements of the structure genomics pipeline.

MECHANISM OF SUPPORT

This RFA will use NIH Specialized Center (U54, Cooperative Agreement) 
award mechanism.  As an applicant, you will have the primary 
responsibility for planning, directing, and executing the proposed 
project.  This RFA is a one-time solicitation.  The anticipated award 
date is July 1, 2005.  This RFA uses just-in-time concepts.  This 
program does not require cost sharing as defined in the current NIH 
Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/master_list.htm .

The NIH U54 is a cooperative agreement award mechanism.  In the 
cooperative agreement mechanism, the Principal Investigator retains the 
primary responsibility and dominant role for planning, directing, and 
executing the proposed project, with NIH staff being substantially 
involved as a partner with the Principal Investigator, as described 
under the section "Cooperative Agreement Terms and Conditions of 
Award."  Plans for this program beyond the 5-year award period are 
indefinite and will be considered by the Institute staff with the 
advice of the NIGMS Council.  Applicants may submit applications in 
response to this RFA for large-scale centers (GM-05-001) and the RFA 
for specialized technology centers(GM-05-002) and the RFA for centers 
for protein structures related to disease (if this  
RFA is published).  If an applicant submits to one or more, the overlap 
must be clearly noted.  Only one award will be made to any applicant.

FUNDS AVAILABLE

The NIGMS intends to commit up to $60 million in FY2005 to fund up to 5 
new large-scale centers in response to this RFA.  An applicant may 
request a project period of up to 5 years and a budget for the first 
year for up to $12 million total costs.  This cap must include all 
costs, such as equipment and indirect costs for subprojects.  Annual 
cost-of-living increases in future years must not exceed 3%.  Because 
the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and 
duration of each award will also vary.  Although the financial plans of 
NIGMS provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications.  

Post-award management:  During the course of the grant period, both 
computational and experimental technologies are expected to improve, 
and the rate of progress and focus of work supported by the grant may 
change.  It is expected that the Principal Investigator will make any 
necessary adjustment in scientific direction to accommodate the 
expected scale-up and changing environment.  The NIGMS staff must be 
kept informed of any significant changes.  In order to ensure that the 
project remains focused on appropriate goals, incorporates new 
technological advances, and makes sufficient progress, scientific and 
programmatic visits to the grantee will be conducted at a frequency to 
be determined by NIGMS staff.  In addition, benchmarks for progress may 
be negotiated annually.

The NIGMS may include outside consultants in the annual progress review 
and reduce or withhold funds for failure to meet milestones agreed upon 
by grantees and NIH staff.  A report by the NIGMS program director on 
each research center's progress and any recommendations to modify 
funding will be made annually to the National Advisory General Medical 
Sciences Council.

ELIGIBLE INSTITUTIONS
 
You may submit an application if your institution has any of the 
following characteristics:

o  For-profit or non-profit organizations 
o  Public or private institutions, such as universities, colleges, 
hospitals, and laboratories
o  Units of state and local governments
o  Eligible agencies of the Federal government  
o  Domestic institutions/organizations
o  Foreign institutions are not eligible to apply but are eligible for 
inclusion as subcontracts with sufficient justification. 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with his/her 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

A. Special requirements for cooperative agreements  

1.  Cooperative Agreement Terms and Conditions of Award

The following section represents Terms and Conditions that will be 
incorporated into the award statement and will be provided to the 
Principal Investigator, as well as to the appropriate institutional 
official, at the time of award.  The following special terms of award 
are in addition to, and not in lieu of, otherwise applicable OMB 
administrative guidelines, HHS grant administration regulations at 45 
CFR Parts 74 and 92 (Part 92 is applicable when State and local 
Governments are eligible to apply), and other HHS, PHS, and NIH grant 
administration policies:

The administrative and funding instrument used for this program will be 
the cooperative agreement, an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH programmatic 
involvement with the awardees is anticipated during performance of the 
activities.  Under the cooperative agreement, the NIH purpose is to 
support and stimulate the recipients' activities by involvement in and 
otherwise working jointly with the award recipients in a partnership 
role; it is not to assume direction, prime responsibility, or a 
dominant role in the activities.  Consistent with this concept, the 
dominant role and prime responsibility for the project as a whole 
resides with the awardees.

2. Principal Investigator

The Principal Investigator is the scientist who assembles the project 
and is responsible for submitting the application in response to this 
RFA and for performance of the project.  The Principal Investigator has 
the overall responsibility for scientific and technical direction and 
for the administration and overall operation of the large-scale PSI 
research center.  Each PSI award must implement approved plans for the 
PSI-2 target selection goals:
Target selection goal #1. Complying with the decisions of the Steering 
Subcommittee on Target Selection for structural coverage of a majority 
of sequenced genes by the determination of representative structures of 
large protein families at coarse granularity.
Target selection goal #2. Carrying out a structural genomics research 
project with a significant biomedical theme.   
Target selection goal #3. Complying with the decisions of the 
Subcommittee on Target Selection for structural coverage at fine or 
coarse granularity of proteins that are proposed by the scientific 
community to the PSI Network.

The Principal Investigator will:
o  Design and direct the large-scale center
o  Design and direct the biomedical theme research project (Target 
selection goal #2) as described in the application
o  Provide goals and milestones for the project consistent with the 
PSI-2 goals
o  Commit a substantial level of effort to the project
o  Participate in the cooperative agreement activities and accept the 
PSI-2 regulations, plans, and decisions
o  Be a member of the PSI Research Network Steering Committee (See 
Special requirement A.6)
o  Attend annual meetings of the Steering Committee and participate in 
its activities, including setting goals and making future plans 
o  Participate in the activities of the PSI Network 
o  Ensure the timely dissemination of information generated by the 
research center to the scientific public
o  Ensure that the structure coordinates and structure factors are 
deposited promptly to the PDB
o  Ensure that results and data are collected, maintained, and 
transferred to appropriate databases, including the PDB; the Target 
Database; and the Protein Expression, Purification, and Crystallization 
Database  
o  Ensure that all appropriate results are provided to the PSI Network 
Knowledge Base
o  Ensure that the center complies with the intellectual property 
policies of the research center, the NIH, and those developed by the 
PSI Network 
o  Ensure that materials generated by the research center are shared 
with qualified scientists 
o  Submit periodic progress reports
o  Appoint an External Scientific Advisory Committee of research 
scientists not involved in the consortium to provide independent 
assessment and advice to Principal Investigator and the research center
o  Manage the Center Development Funds, subject to NIH program director 
approval.

3. PSI Network Director

The PSI Network Director is an NIH extramural staff individual who has 
leadership responsibilities for the management and coordination of the 
PSI Network.  The PSI Network Director is not a member of the Steering 
Committee and does not direct the scientific activities of the PSI 
Network centers (whose direction is the responsibility of the Principal 
Investigator).  The PSI Network Director will also:
o  Provide advice to the PSI Network Steering Committee on the overall 
direction of the PSI and on meeting the PSI goals and milestones
o  Report on the PSI Network activities and progress to the director of 
NIGMS, the NIGMS Council, and advisory councils for other participating 
NIH institutes and centers
o  Appoint members and a chair of the PSI Advisory Committee, following 
consultation with the director of NIGMS
o  Evaluate and implement the advice of the PSI Advisory Committee and 
the PSI Network Steering Committee for allocating NIH support and 
revising and setting policy
o  Facilitate communication with the scientific community directly 
affected by the PSI
o  Ensure that the Steering Committee and the PSI Advisory Committee 
address issues and concerns raised by the community.  
o  Call and coordinate meetings of the Steering Committee and the PSI 
Advisory Committee
o  Select appropriate additional programs to be added to the PSI 
Network as non-voting members of the Steering Committee.

4. NIH Program Directors

The NIGMS Program Directors are the extramural staff individuals who 
provide normal program stewardship for the PSI Network center awards.  
The NIH Program Directors are not members of the Steering Committee and 
do not direct the scientific activities of the PSI Network centers 
(whose direction is the responsibility of the Principal Investigator).  
The NIH Program Directors will also:
o  Negotiate milestones and goals on throughput and costs with the 
grantees
o  Attend all meetings of the Steering Committee
o  Prepare annual reports on the progress of PSI-2 research centers
o  Provide information to the research center Principal Investigators 
on activities and policies of the PSI Network and the NIH
o  Recommend appropriate budgets for the research centers, including 
withholding or reduction of support for failure to meet milestones 
and/or other terms or conditions.

5. NIGMS/NIH Scientific Liaisons

The NIH Scientific Liaisons are representatives of the NIH extramural 
staff who serve on the Steering Committee and have substantial 
scientific/programmatic involvement in the project that is above and 
beyond normal program stewardship.  Each of the NIH institutes and 
centers supporting a PSI Network center will have one Scientific 
Liaison.  In addition, one member of the NIGMS staff will serve on the 
Steering Committee and the Steering Subcommittee on Target Selection 
This position will be named the Scientific Liaison for Target 
Selection.  The Scientific Liaisons will also:
o  Serve as voting members of the Steering Committee and attend all 
meetings
o  Assume a substantial coordinating role on the Steering Committee
o  Make recommendations to the Steering Committee based upon their 
knowledge of other, related NIH-supported research and resource 
activities
o  Facilitate interactions among the Steering Committee, the PSI 
Advisory Committee, and NIH staff
o  Provide advice and guidance to the Steering Committee to assure that 
the PSI project adheres to the NIH/NIGMS rules and regulations
o  Take on additional responsibilities as negotiated at the time of 
award.
 
6. Steering Committee

This committee is the main governing body of the Protein Structure 
Initiative Research Network.  Membership will include the Principal 
Investigators of the large-scale centers, the Principal Investigators 
of the specialized centers, the NIH Scientific Liaisons, a 
representative of the Protein Data Bank, a representative of the PSI 
Network Knowledge Base, and other scientists chosen by the above 
members.  The NIGMS/NIH Scientific Liaisons will serve as voting 
members of the Steering Committee and attend its meetings.  Total NIH 
representation on the Steering Committee will make up no more than 40% 
of the voting members.  Other members of the NIH staff may also attend 
the Steering Committee meetings.  The Principal Investigators of other 
related structural genomics projects may be added to the Steering 
Committee as non-voting members, as determined appropriate by the PSI 
Network Director.  The Steering Committee will:
o  Meet at least annually with the PSI Advisory Committee and the NIGMS 
staff to discuss progress of the PSI Network in reaching the goals set 
by the NIGMS/NIH staff and Councils and in meeting the needs of the 
scientific community
o  Elect a non-NIH chair to serve a 2-year term
o  Prepare and publish annual reports on progress in meeting milestones 
and goals of the PSI
o  Develop procedures and policies on PSI Network activities, including 
laboratory information management systems, data management and 
deposition, publications, reports, etc. for consideration by the PSI 
Advisory Committee and the NIGMS Council
o  Communicate with the scientific community on scientific and 
technological achievements
o  Organize and appoint a subcommittee on target selection 
o  Serve as the body for coordinating and making decisions on target 
selection
o  Serve as the body for coordinating and making decisions to ensure 
meeting the milestones and goals for the production phase of the PSI
o  Organize and appoint appropriate subgroups to address related 
issues. 

7. Steering Subcommittee on Target Selection

This subcommittee will be composed of the Principal Investigators of 
the large-scale centers, the Scientific Liaison for Target Selection, 
and other representatives as chosen by the Steering Committee.  Program 
Directors of the Specialized centers will serve as liaisons to the 
Steering Subcommittee for target selection.  The subcommittee will 
coordinate the selection of protein targets among the large-scale 
centers.  This subcommittee will do the following:
o  Elect a non-NIH chair to serve a 2-year term.
o  Obtain appropriate scientific and technical assistance for the 
various tasks related to target selection
o  Incorporate targets chosen by the specialized centers into the list 
of targets for the PSI Network
o  Develop a list of targets of representatives from large protein 
families to meet the PSI-2 goals for structural coverage of sequenced 
genes at coarse granularity (Target selection goal #1)
o  Develop a list of targets of representative protein families for the 
biomedical theme project for structural coverage at coarse or fine 
granularity to meet the PSI-2 goals (Target selection goals #2 and #3).  
This activity has two parts:
1.  Develop a process for soliciting suggestions from the scientific 
community for groups of proteins for consideration for structural 
coverage at coarse or fine granularity (Target selection goal #3)
2.  Develop a process for integrating targets chosen by the large-scale 
centers for their biomedical theme projects (Target selection goal #2) 
with those from the scientific community (Target selection goal #3)
o  Develop a process for utilizing each center’s structural genomics 
pipeline for: (1) coarse granular coverage of sequenced genes (60-70%), 
(2) fine or coarse granular coverage of the biomedical theme projects 
chosen by the center(15-20%), and (3) fine or coarse granular coverage 
of the proteins proposed by the scientific community (15-20%)
o  Develop a final list of targets for the PSI Network
o  Coordinate target selection for protein production and structure 
determination at the large-scale centers
o  Report to the Steering Committee on these plans for target 
selection.
  
8. PSI Advisory Committee

The PSI Advisory Committee is a working group of the NIGMS Council.  It 
will advise the Council on the management, progress, and plans for the 
PSI.  This committee will:
o  Meet at least once a year with the Steering Committee and NIH staff 
prior to the submission of the annual progress report 
o  Examine and comment on target selection policy and progress toward 
milestones
o  Provide advice to the Principal Investigators and Steering Committee 
about meeting the PSI goals and plans for future directions
o  Raise issues for consideration by the Principal Investigator and the 
Steering Committee 
o  Comment on the appropriateness of the level of NIGMS support to 
achieve the goals of the project.

9. Goals and Milestones

The PSI-2 will have annual milestones appropriate to the 5-year goal.  
Milestones will be determined through discussions with the Principal 
Investigators, Steering Committee, and NIH staff.  The milestones and 
goals will be refined annually with input from the Steering Committee 
and PSI Advisory Committee.    

10. Reports

The PSI Network Steering Committee will produce an annual report on the 
progress made toward the annual milestones and goal.  The report will 
be delivered to the NIGMS staff and PSI Advisory Committee within one 
month of the annual meeting.
  
11. PSI Arbitration Panel

A panel formed as needed to review scientific or programmatic 
disagreements (within the scope of the award) that may arise between 
the PSI Network and the NIH.  It will be composed of three members:  a 
designee of the Steering Committee chosen without NIH staff voting, one 
NIH designee, and a third designee with expertise in the relevant area 
who is chosen by the other two.  

(End of cooperative agreement terms)

B. PSI Research Center special requirements

The NIGMS has adopted several polices that are applicable to these PSI 
large-scale research centers.  Applicants must present plans to adhere 
to the policies, where appropriate.

1. Data Release and Sharing of Results and Materials.  The PSI 
represents a major scientific endeavor with large amounts of data 
generated in the process of protein structure determination.  The 
primary products of the PSI, structural coordinates, must be deposited 
promptly in the PDB, which has served the scientific community for four 
decades by providing public access to the annotated structural models.  
Other structural results, including, structure factors, must also be 
deposited promptly into the PDB.  Although guidelines developed by NIH 
for research grants 
(http://grants.nih.gov/grants/guide/notice-files/not99-010.html) 
permit NIH Principal Investigators to deposit coordinates and structure 
factors upon publication of results, PSI regulations and programmatic 
goals are more stringent and require these depositions upon completion 
of the structures.  For the start of PSI-2, this will be interpreted as 
receipt by the PDB within four weeks of the coordinate refinements.

In addition, dissemination of results of the large-scale research 
centers is crucial to the programmatic goals of the PSI, and applicants 
should plan on sharing findings and their experiences at the annual 
meetings for structural genomics grantees and in other appropriate 
forums.  This includes information on strategies for target selections, 
status of research on these proteins, technological and methodology 
findings, high-throughput approaches, efficiency, and cost analyses.  
Grantees will be required to develop and maintain a public website 
showing the information listed above, as well as providing it in their 
annual progress reports.  These results must be provided to the PSI 
public website, which contains information on the program and technical 
and scientific results.  

Another database, TargetDB (See TargetDB at http://targetdb.pdb.org/), 
was recently developed by PDB with PSI and contains all the PSI 
centers  targets and weekly progress toward structure determination.  
This information should avoid duplicative work and assist planning by 
the centers and other structural labs.  The current PSI pilot centers 
are required to provide these data for uploading each week, and this 
policy will continue in PSI-2.  TargetDB has increasingly attracted 
attention of the scientific community.

The PSI is currently developing a database for deposition of 
information on experimental outcome data (both successful and 
unsuccessful).  These data include genome analysis for protein 
clustering and target selection, cDNA cloning, expression vector 
construction, protein production and purification, protein biochemical 
characterizations, crystallization screening, synchrotron and NMR data 
collection, etc.  The PSI Research Network centers will be required to 
provide plans for the collection, maintenance, and transfer of 
experimental results into this central data repository.  This database, 
named the Protein Expression, Purification, and Crystallization 
Database (PepcDB), is under development and will contain information on 
these important results and provide a platform for cross-center data 
mining to capitalize on the PSI investment (contact Dr. Norvell at 
NIGMS for updated information).  

In some cases, the proteins and samples generated by these research 
centers will need to be pursued by detailed functional studies by 
scientists both within and outside the research centers that are beyond 
the scope of these awards.  The research centers will be required to 
provide these materials to appropriate investigators.  Currently the 
individual pilot centers have the responsibility for distribution of 
these proteins and samples, but a centralized repository is being 
considered for PSI-2.   

In PSI-2, the PSI Advisory Committee and NIGMS staff anticipates the 
need for a central resource that interconnects all the data and 
resources generated by the PSI with related databases and other 
biological information.  This resource has been named the PSI Network 
Knowledge Base.  The PSI research centers will be required to make all 
data available for dissemination by the PSI Knowledge Base. 

2. Management Plan.  The management of a PSI large-scale research 
center requires a significant commitment by the senior staff.  The 
Principal Investigator must devote a substantial effort to the project.  
The applicant must propose a management plan that takes into account 
the changes that will occur over the 5-year term of the award. If the 
requested budget includes Center Development Funds (See Special 
requirement B.9), the applicant must explain how decisions on the use 
of these funds will be made by the Principal Investigator and the 
senior staff of the center.  

3. Research Training.  Applicants must have plans for research training 
activities.  One example is the involvement of graduate students and 
postdoctoral associates as part of the research staff.  Although many 
PSI activities involve extensive data collection and therefore might 
not be appropriate as research training projects, other activities will 
be at the cutting edge of research and thus would be suitable for 
graduate thesis research training and for postdoctoral projects.   
Another example of a research training activity is the organization of 
technical workshops for graduate students and postdoctoral associates 
as potential users of the pipeline, materials, and PSI results.  

4. Participation of underrepresented minority investigators and 
students.  The research centers must have plans to promote the 
participation of investigators and/or students from underrepresented 
minority groups. One example is the organization of summer programs for 
faculty and/or students from minority institutions.  Another example is 
the solicitation of protein targets from faculty at minority 
institutions for inclusion in the center’s structural genomics pipeline 
and target selection process.

5. Participation of the scientific community.  The primary 
responsibility of the large-scale PSI centers is the operation of a 
structural genomics pipeline to meet the PSI goals on production of 
unique protein structures.  The deposition of coordinates and other 
results are the main service provided to the scientific community, but 
the substantial public funds invested in these centers carry an 
obligation for further service to scientists interested in the 
production of proteins and protein structures.  Research center 
applicants must have plans for activities for participation of the 
scientific community.  For example, centers could designate a limited 
period of time for the incorporation of special projects from outside 
scientists into the structural genomics pipeline.  Centers could plan 
for short-term courses and technical workshops for potential users of 
the pipeline, materials, and PSI results.

6. Intellectual property.  NIGMS is committed to making results of 
these projects freely available for use by the entire research 
community and, therefore, released into the public domain.  Applicants 
should present plans related to intellectual property rights consistent 
with this policy.  The NIGMS will monitor its grantees' activities with 
respect to patenting the structural results and technology 
developments.

The scientific review group will comment, as appropriate, on the plans 
and previously demonstrated success for handling intellectual property 
issues.  Since dissemination of results is a critical aspect of the 
PSI, evidence of the commitment to the sharing of research resources 
and to effective management of intellectual property issues will be 
part of the scientific merit review, as well as an important factor in 
the Institute’s decision to make an award.  Furthermore, these plans, 
after negotiation with the applicant when necessary, will be made a 
condition of the award.  Evaluation of annual progress reports and of 
subsequent renewal applications will include an assessment of the 
effectiveness of the sharing of research resources and managing 
intellectual property issues.

Plans for sharing of research resources and intellectual property must 
make unique research resources readily available for research purposes 
to qualified individuals within the scientific community in accordance 
with the NIH Grants Policy Statement 
(http://grants.nih.gov/grants/policy/nihgps/) and the Principles and 
Guidelines for Recipients of NIH Research Grants and Contracts on 
Obtaining and Disseminating Biomedical Research Resources: Final Notice, 
December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and 
http://ott.od.nih.gov/NewPages/64FR72090.pdf).  These documents also 
define terms, parties, responsibilities, prescribe the order of 
disposition of rights, prescribe a chronology of reporting requirements, 
and delineate the basis for and extent of government actions to retain 
rights.  Patent rights clauses may be found at 37 CFR Part 401.14 and 
are accessible from the Interagency Edison web page, 
http://www.iedison.gov.

7. External Scientific Advisory Committee.  Each research center should 
have an external scientific advisory committee of research scientists 
not involved in the consortium to provide independent assessment and 
advice to the Principal Investigator of each research center and 
his/her staff.  This committee should be appointed by the Principal 
Investigator and meet at least once each year.  In order to maximize 
the pool of possible reviewers, the potential (or new) members of the 
external scientific advisory committee should not be contacted or 
selected until after an award has been made.

8. Annual PSI Meeting.  The Principal Investigator and appropriate 
staff of each PSI large-scale research center will be expected to 
attend the PSI annual meeting and workshops to discuss progress and 
results.

9. Center Development Funds.  This budget item will provide budgetary 
flexibility in the development and operation of the structural genomics 
pipeline for producing proteins and determining their structures.  It 
will permit the large-scale centers to make budget changes within a 
budget year and to explore innovative ideas and new technologies.  
Since reallocation during any budget year between subprojects (often at 
different institutions) is difficult, the Center Development Fund may 
be needed by a large-scale center to make major changes and move in new 
directions.  The primary use of these funds must be to support staff 
and purchase equipment and supplies related to the pipeline tasks.  New 
technology and methodology development projects to improve the 
structural genomics pipeline are also appropriate.  Applicants may 
request up to 5% of the total budget annually as a Center Development 
Fund.  If these funds are requested, the applicant must provide an 
explanation of the process that the center will use to determine its 
allocation.  All expenditures from the Center Development Fund will 
require NIH staff approval.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o  Direct your questions about scientific/research issues to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0533 
FAX: (301) 480-2004 
Email: [email protected]  

o  Direct your questions about peer review issues to:

Helen R. Sunshine, Ph.D. 
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-2881
FAX:  (301) 480-8506
Email:  [email protected]

o Direct your questions about financial or grants management matters 
to:

Ms. Grace Olascoaga
Division of Extramural Activities
National Institute of General Medical Sciences
Building 45, Room 2AN.32E, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5520
FAX:  (301) 480-2554
Email: [email protected]
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o  Descriptive title of the proposed research
o  Name, address, and telephone number of the Principal Investigator
o  Names of other key personnel 
o  Participating institutions
o  Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by September 10, 2004 to:

John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0533 
FAX: (301) 480-2004 
Email: [email protected]  

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements.  The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/.  The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form.  The PHS 398 document is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].

SUPPLEMENTARY INSTRUCTIONS:

Special application requirements

The research center should be an integrated, coordinated project, with 
various interdependent subprojects that comprise structural genomics as 
described above.  The subprojects should be organized to be consistent 
with the seven components of structural genomics that were listed above 
in the section "Research Objectives.C".  They must be fully described 
and justified.  The center must also meet the SPECIAL REQUIREMENTS 
B.PSI Research Center Special requirements.  Collaborations and 
consortia are encouraged.  In such collaborations, the respective 
contributions should be well integrated into the design of the 
application.  An overview section should be prepared that includes an 
overall description that defines the scope and objectives.

The application should have a face page; abstract; project overview 
(which describes the overall program and defines its scope and 
objectives); project rationale; subproject descriptions; consolidated 
budget; listing of key personnel; subproject budgets; biographical 
sketches; investigators' other support; institutional support, 
resources and facilities; and letters of collaboration.  Applications 
should include a separate cover sheet that lists 1)all participants, 
including consultants and private sector alliances, 2) all the 
institutional affiliations for each participant, and 3) their roles on 
the project and whether new or continuing (if applicable).  This 
requirement will facilitate the review of applications.

The budget should be no greater than $12 million total costs for the 
first year, with annual cost-of-living increases (not to exceed 3%) in 
subsequent years.  The budget should be fully justified and should 
include funds for attending the PSI annual meetings, workshops, 
Steering Committee meetings, and other PSI meetings.  The page limit 
for the research plan (including project overview, project rationale, 
and subproject descriptions) is 70 pages total.

The application should provide plans and assurances that the center 
will: 
o  Participate in the target selection process of the PSI Network
o  Meet the production goals of the PSI Network 
o  Carry out the work agreed to by the Steering Committee (Target 
selection goals #1 and #3)
o  Submit data to the PSI Network Knowledge Base.
 
The application should describe future plans and previously 
demonstrated success for:
o  Protein family classification and target selection, including their 
applicability to the goals of the PSI Research Network 
o  Producing and determining a large number of unique, non-redundant 
protein structures in high-throughput operation
o  Methodology and technology development relevant to structural 
genomics
o  Increasing throughput, efficiency, and success rates and decreasing 
costs for producing and determining the structures of proteins
o  Operation of a high-throughput structural pipeline that includes all 
constituent tasks
o  Effective management and administration of a research center or 
other large research program (including plans for management of the 
Center Development Fund, if this was requested in the budget)
o  Sharing of results and prompt placement of data in the public 
domain, including deposition of coordinates and structure factors in 
the Protein Data Bank
   
The application should describe plans for:
o  Carrying out the scientific goals of the center for the biomedical 
theme project designed to focus on protein structures for specific 
pathways, organisms, and/or groups  (Target selection goal #2) 
o  Analyses of structures for biomedical significance and dissemination 
of results
o  Developing annual milestones and evaluations for the center and as a 
component of the PSI Network
o  Sharing materials generated by this research 
o  Handling intellectual property issues for the center consistent with 
the NIGMS/NIH policies 
o  Submitting target data and progress to the TargetDB and releasing 
cloning, protein production, and crystallization results into PepcDB.   
o  Providing resource sharing and training to the scientific community.
o  Producing and determining unique, non-redundant protein structures 
from one or more classes of challenging proteins.

The application should provide data on unique, non-redundant protein 
structures that have been solved by the participating investigators 
during the past five years.  If an investigator has solved few or no 
unique, non-redundant protein structures, provide data for all 
structures solved for that investigator during the past five years.  
These data should include the following information:
o  PDB access code and submission date
o  Molecular weight
o  Most closely related protein in the PDB (give the identity of the 
protein and the sequence identity)
o  Size of the sequence family (number of proteins that could be 
modeled)
o  For structures determined by crystallography, give the resolution 
and R-factor
o  For structures determined by NMR, give the number of meaningful 
restraints per refined residue and the rms deviation to the mean 
structure for backbone and all heavy atoms
o  Information on function and other relevant information.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application. Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/labels.pdf.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application and 
all copies of the appendix material must be sent to:

Helen R. Sunshine, Ph.D. 
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-2881
FAX:  (301) 480-8506
Email:  [email protected]

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by NIGMS.  Incomplete applications will not be 
reviewed.  

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by NIGMS in accordance with the review criteria 
stated below.  As part of the initial merit review, all applications 
will:

o  Undergo a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the 
applications under review, will be discussed and assigned a priority 
score
o  Receive a written critique
o  Receive a second level review by the National Advisory General 
Medical Sciences Council 

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, provide valuable research resources to the 
scientific community, improve the control of disease, and enhance 
health.  In the written comments, reviewers will be asked to evaluate 
the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  
The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, 
weighting them as appropriate for each application. 

o  Significance 
o  Approach 
o  Innovation
o  Investigator
o  Environment

SIGNIFICANCE: What is the likelihood that the applicant will operate a 
successful large-scale, high-throughput research center and meet the 
goals of PSI-2?   Will be the technology and methodology development of 
the research center be significant?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of 
the project? Are the plans for organization of the center appropriate? 
Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  Are the plans and milestones appropriate?

INNOVATION: Does the project employ novel and innovative concepts, 
approaches or methods?  Will the project develop new methodologies or 
technologies?  How exportable are the strategies and technologies that 
will be developed by this center?  

INVESTIGATORS: Are the investigators appropriately trained and well 
suited to carry out this work? Is the work proposed appropriate to the 
experience level of the Principal Investigator and other researchers?  
Does the Principal Investigator have the appropriate management and 
administrative skills?  

ENVIRONMENT: Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of adequate institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

o  Plans and previously demonstrated success for protein family 
classification and target selection, including plans for their 
applicability to the goals of the PSI Research Network
o  Plans and previously demonstrated success in producing and 
determining unique, non-redundant protein structures in a high-
throughput operation
o  Plans and assurances that the center will carry out the work 
assigned by the Steering Committee (Target selection goals #1 and #3) 
and meet the production goals of the PSI Research Network
o  Plans and previously demonstrated success in increasing throughput, 
efficiency, and success rates and decreasing costs for producing and 
determining the structures of proteins
o  Plans and previously demonstrated success in developing innovative 
methodologies and technologies for the production and structural 
determination of proteins
o  Merit of the center’s research project with a significant biomedical 
theme (Target selection goal #2) and plans for accomplishing it
o  Plans for producing and determining unique, non-redundant protein 
structures from one or more classes of challenging proteins
o  Plans and previously demonstrated success in operation of a high-
throughput structural pipeline that includes all constituent tasks
o  Plans and previously demonstrated success for handling intellectual 
property issues, for sharing results and materials generated by this 
research, and for prompt placement of data in the public domain, 
including deposition of coordinates in the Protein Data Bank and 
placement of appropriate data in the PSI Network Knowledge Base
o  Plans and previously demonstrated success for managing a large 
research project (including plans for management of the Center 
Development Fund, if this was requested in the budget).

ADDITIONAL REVIEW CONSIDERATIONS

Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research must include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the 
reviewers.  However, reviewers will not factor the proposed data 
sharing plan into the determination of scientific merit or priority 
score. (http://grants.nih.gov/grants/policy/data_sharing )

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: September 10, 2004
Application Receipt Date:  October 15, 2004
Peer Review Date:  February/March 2005
Council Review:  May 2005
Earliest Anticipated Start Date:  July 2005

AWARD CRITERIA

Criteria that will be used to make award decisions include:

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Programmatic priorities, including the uniqueness and contribution 
of the proposed center to the overall goals of the PSI-2.

REQUIRED FEDERAL CITATIONS 

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule.  

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations.  Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.  Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284)(cite appropriate authorizations) and 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite 
relevant regulations).  All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care, or early childhood development services are provided to 
children.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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