Concept Clearance: High-Throughput Structural Biology

January 23, 2009

Proposed new NIGMS research and training programs are made public at the open session of National Advisory General Medical Sciences Council meetings. Council approval of new initiatives (and major changes to existing initiatives) is called "concept clearance." Concept clearance authorizes NIGMS staff to develop plans, publish announcements in the NIH Guide for Grants and Contracts, and fund grants. During the initiative planning stages that follow concept clearance, NIGMS welcomes comments and suggestions from the community.

At its January 2009 meeting, the Council discussed the concept clearances summarized below.

High-Throughput Structural Biology

The goal of PSI: High Throughput Structural Biology (PSI:HTSB) will be to test whether the new paradigm of high-throughput structure determination via highly organized networks of investigators can be applied to a broad range of biological problems.

It will consist of five main components established through RFAs with set-aside funds soliciting Cooperative Agreements:  1) Centers for High-Throughput Structure Determination; 2) Centers for Membrane Protein Structure Determination; 3)  Consortia for High-Throughput Enabled Structural Biology Research; 4) the PSI-SG Knowledgebase; and 5) the PSI-SG Materials Repository; plus three additional components supported through on-going PARs with no set-aside funds: 1)  Technology Development for HT-Structural Biology Research; 2) Technology Development for Protein Modeling; and 3) High-Throughput Enabled Structural Biology Research.

The vision is that these various components will operate together as a network:

Requests for Applications

• The Centers for High-Throughput Structure Determination (RFA #1) will have five main functions: i) determination of protein structures utilizing high-throughput pipeline capabilities; ii) development of technology to improve the pipeline and to attack increasingly difficult proteins and complexes of proteins at high-throughput; iii) bioinformatics analysis of potential targets, solved structures, and the creation of models based on solved structures; iv) dissemination of information and materials via the Materials Repository and Knowledgebase; and v) collaborative research with other members of the network to be established through this and the other RFAs and PARs that are part of this initiative.  These centers would receive the majority of their operating budgets directly through RFA #1.  This budget would primarily support core activities of the center, including support of collaborative research to be solicited through RFA #3 and the solution of community nominated targets; and would secondarily support continuing work on coverage of sequence space and any biological theme project associated with the center.  The centers would receive additional budget components through the remaining programs of the initiative to enable them to scale up specific activities to meet the needs of their collaborators.  Overall activities of these centers are expected to be 70% collaborative research in conjunction with awards issued through RFA #3, 15% biological theme research, and 15% sequence coverage and technology development related research.  In addition to depositing vectors and clones into the Materials Repository, it is expected that the centers will make proteins available for investigations that complement their structural studies.
• The Centers for Membrane Protein Structure Determination (RFA #2) will focus on the solution of membrane protein structures of high biological interest and on the development of new methods expected to render membrane protein structures more amenable to high-throughput determination.  Within the realm of membrane protein structures, these centers will have similar responsibilities to the above centers for: i) determination of structures; ii) development of technology; iii) bioinformatic analysis and modeling to leverage solved structures; iv) dissemination of information and materials; and v) collaborative research.  These centers, however, will receive the major component of their budget through RFA #2, with lesser amounts expected to come through collaborative arrangements.  Overall activities of the membrane protein centers are expected to be 70% research on biological targets proposed by the centers and 30% on targets developed through collaborations solicited through RFA #3 and community target nominations.
• High-Throughput Enabled Structural Biology  Partnerships (RFA #3) will have the primary purpose of ensuring that a broad community of scientists participates-in and benefits from high-throughput structural biology.  Proposals will be solicited from individuals and groups of scientists who are not associated with the above centers (established by RFA #1 and RFA #2) and will propose to collaborate with the network as a whole, not a single specific center.  Individuals affiliated with the above centers (established by RFA #1 and RFA #2) may also participate in these proposals, but may not be the sole or dominant group of investigators.  Scientific problems proposed should be able to effectively make use of the HT-capabilities of the centers or provide a driver for further technology development.  These consortia are expected to include functional characterization of novel proteins primarily outside of the structure determination centers as well as novel structure determinations within these centers and thus provide a key link between a structure and its biomedical impact.  Budgets and durations of these projects (typically 2-5 years; average = 3 years) will vary depending on scope as will the division of funds to support activities within the above centers and activities outside the centers.  In general, less than half of the collaborative budget will go to support structural center operations.  Investigators participating in these consortia are expected to abide by the PSI rules regarding identification of targets and distribution of materials and results.  Co-funding by other Institutes and Centers of the NIH for structural studies relevant to their missions will be solicited.
• The PSI-SG Knowledgebase (RFA #4) will play an increasingly important role in information dissemination and coordination of activities across the network.  It will continue to provide information on targets, project progress, materials and methods, raw structure data and coordinates via the PDB, enhanced annotation of protein function, a portal to models generated from existing experimental data, and additional links.  It will provide the community access to nominate targets for structure determination and will continue to foster an awareness of structural genomics and structural biology to the wider scientific community.
• The PSI-SG Materials Repository (RFA #5) will continue to play a key role to provide centralized collection, maintenance, storage, and distribution of vectors and clones generated by the PSI..  As more clones and structures are produced, the PSI-MR will continue to serve and enable researchers throughout the country and the world to receive access to these valuable reagents.

The above components will form the core of the PSI Network for High-Throughput Structural Biology.  As cooperative agreements, the network will be managed by representatives from all of its components and by NIH staff.

Program Announcements

Recognizing that not all of the best ideas may be ready on a single RFA receipt date or present only in large scale centers, and recognizing the need for continued support of some projects evolving from the current specialized centers, it is planned to issue of series of PARs (program announcements with on-going receipt dates  and dedicated review venues, but no set aside funds) to allow for the fluid addition of new projects and investigators to the network as opportunities emerge.  These PARs will provide for on-going peer review of proposals using traditional (R21, R01, and P01) grant mechanisms for investigators who wish to conduct research in association with the network.

• Technology Development for HT-Structural Biology Research (PAR #1) is particularly still needed for the study of membrane proteins, proteins that form complexes, nucleic acids, and protein-nucleic acid complexes, and for improvements to the technology for high-throughput operations.
• Technology Development for Protein Modeling (PAR #2) is needed to improve the leverage of experimentally determined structures, to improve ability to solve structures with partial experimental datasets, and to make modeling more accessible and transparent to non-experts in the field.
• High-Throughput Enabled Structural Biology Research (PAR #3) opportunities are expected to ripen over time as the broader community becomes aware of the opportunity.  It is critical that the door remain open for new projects to gain access to the latest high-throughput capabilities.  Projects responsive to this PAR will be similar to those solicited through RFA #3.

These awards would include a mix of R21, R01, and P01 awards.  The applications might or might not build on existing collaborations in the network.  Independent projects would be welcomed, but investigators would be expected to participate in network activities.  In many cases conversion to cooperative agreement mechanisms may be warranted.

The proposed budget and time-line for these RFAs and PAs is attached.

The rationale for developing these initiatives and the scientific opportunities to be addressed are discussed in the report of the Future Structural Genomics Initiatives meeting and the recommendations section of the annual report of the Protein Structure Initiative Advisory Committee.

Timeline for Implementation of Initiatives

Centers for High-Throughput Structure Determination (RFA #1)
Centers for Membrane Protein Structure Determination (RFA #2)
High-Throughput Enabled Structural Biology Partnerships (RFA #3)

RFAs #1-3 will be competed at the same time to enable highly coordinated review and funding decisions to be made.  These RFAs will be announced with as long a lead time between announcement of the funding opportunity and receipt date as possible to allow investigators time to organize themselves into appropriate research teams.  Awards will be made in FY2010 for a period of 5 years.

RFA Release Date:  April, 2009
RFA Briefing Meeting:  June, 2009
Letters of Intent Due:  September, 2009
Receipt Date:  October, 2009
Review:  Feb/March, 2010
Council Review:  May, 2010
Award:  July, 2010

PSI-SG Knowledgebase (RFA #4)
PSI-SG Materials Repository (RFA #5)

RFA #4-5 will be competed independently since it is not expected that many applications will be received and the subject matter does not require as extensive coordination.

Technology Development for HT-Structural Biology Research (PAR #1)
Technology Development for Protein Modeling (PAR #2)
High-Throughput Enabled Structural Biology Research (PAR #3)

PARs #1-3 will be issued for receipt dates beginning with the same Council round as for RFAs #1-3, but will remain open for three years.  The first awards will be made in FY2010.

PAR Release Date:  June, 2009
Receipt Dates:  October, February, June, 2009-2012
Review:  Feb/Mar, June/July, Oct/Nov, 2010-2012
Council review:  May, September, January 2010-2013
Award:  July 2010 – April 2013

Calendar View of Timeline for Implementation of Initiatives

      *RFA applications will be awarded in FY2010 from set-aside money for the specified centers and collaborating partnership cooperative agreements.
    **PAR figures are estimates of awards that will be paid over the course of several years beginning in FY2010 with no specific funds set-aside assuming a mix of R01 and P01 applications are received. 
  ***FY2009 Estimate.  FY2008 Actual = $68.1 M total costs.
****Sum of minimum expected budget amounts.  Expected actual maximum is much less than the sum of the individual component maximums.