Structured Discussion/Study Questions

Addressed in part during speaker presentations
Session I. Basic Information about the PSI
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  1. What have been the mechanisms of support and management of the PSI?
  2. How much has been invested in the PSI relative to other areas of NIH investment?
  3. What were the conclusions of the PSI assessment and what actions have been taken since the assessment to address concerns?

Speakers: Jeremy Berg and John Norvell
References:
Basic Administrative Information - Tab 8; RFAs - Tab 9.A
PSI Assessment Report, Intro, and Commentary - Tab 9.B, C, D

Session II. Current Status and Future of the PSI
 

Large Scale Centers, Specialized Centers, PSI Materials Repository, and PSI Structural Genomics Knowledgebase

  1. What have been the accomplishments of the PSI to date?
  2. What are the technological capabilities of the PSI centers?
  3. What types of materials and information have been produced and are they being utilized by the community at large?
  4. What opportunities exist for utilizing the infrastructure developed by the PSI centers?

Speakers: Ian Wilson, Wayne Hendrickson, Joshua LaBaer, Helen Berman
References:
PSI Investigators' White Paper - Tab 7 - Progress Reports
PSI Meeting Reports and Advisory Group Summaries - Tab 9. E, F, G, H, I

Homology Modeling and the Use of Models

  1. For what types of problems are current homology models of sufficient accuracy for a given level of sequence identity?
  2. Are the developers of new methods for homology modeling making use of the output of the PSI? If yes, how dependent are they on this source of new structures? If no, why are they not making better use of the PSI structures?
  3. How much improvement in modeling can be expected during the next few years and what are the primary obstacles to improvement?
  4. How can models and modeling expertise be made more readily available to non-expert users?

Speakers: Andrej Sali and Catherine Peishoff.
References:
a) PSI Investigators' White Paper - Tab 7 - Section by Burhard Rost and Adam Godzik.
b) Report of Workshop on Applications of Protein Models in Biomedical Research by Torsten Schwede and Andrej Sali - Tab 9.R.

Advisory Committees and Operations Management of the PSI

  1. Has progress of the PSI generally been satisfactory?
  2. What activities and structures of the PSI have worked well? What has not worked well?
  3. What has been the level of PSI oversight and is it the right level?
  4. Has the level of interaction with NIGMS staff been adequate and appropriate?
  5. What recommendations would you make for the organization of future structural genomics initiatives?

Speaker: Lila Gierasch - PSI Advisory Committee Member
References:
Basic Administrative Information - Tab 8.
PSI Advisory Committee Meeting and Update - Tab 9.F

Session III. Future Directions in Structural Genomics Discussions

 

Topic 1. Structural Genomics - Progress, Done, Doable?

  1. What size is sequence space and how is it changing? What is the size of protein structure space and how is it changing? What are the relationships between sequence space, structure space, protein fold space, and protein family space?
  2. What is the current status with respect to coverage of protein structure space? How many families of what sizes exist for given definitions of a family? For how many of these are example structures known? For how many domains? For how many protein structures? What priority should be given to continuing the original goals of the PSI-2?
  3. Would a more focused approach be more or less useful and how long will it take to achieve various milestones for structural coverage?
  4. What percentages of which genomes are currently covered by known structures for given levels of sequence identity and model accuracy? This should be addressed for the human genome, the top ten model organisms, and other selected organisms or systems of interest, such as key pathogens or specific organelles. What opportunities exist for future activities?

Speaker: John Moult
References:
PSI Investigators' White Paper - Tab 7.
Novel Leverage of Structural Genomics - Tab 9.Q
PSI Statistics update provided by Burkhard Rost - Tab 9.Q
The Nature of the Protein Universe by Michael Levitt - Tab 9.T


Topic 2. Metagenomics

  1. Will metagenomics contribute more to growth in the number of novel single domain families or more to growth in the size of families of already known domains?
  2. How much is metagenomics expected to contribute to the growth of novel single domain families compared to other sources of sequence information?
  3. How valuable will structures from metagemomic sequencing efforts be if the species of origin is unknown?
  4. Will fragments of proteins be of value if the entire coding gene is not know?
  5. What priority should be given to human commensual organism metagenomics versus environmental metagenomics?

Speaker: Claire Fraser-Liggett
References:
PSI Investigators' White Paper - Tab 7.
PSI Statement on the Knowledgebase Website - Tab 9.L
Other Metagenomic References - Tab 9.L

Topic 3. Functional Structural Genomics

  1. NIGMS supported structural genomics efforts to date have focused primarily on the determination of structures. What can be done to enhance the connection between these structures and their functions?
  2. What experimental and theoretical approaches can be taken to assign functions to proteins of unknown function that utilize the solved protein structure?
  3. What can be done to improve the utilization of data from structural genomic programs by the research community at large?
  4. What important questions about protein structure and function could be further facilitated by structural genomics initiatives?

Speakers: Frank Raushel, Jacquelyn Fetrow
References:
Hermann, et al. - Tab 9.C - Articles cited in Assessment Report
A Protein Structure (or Function?) Initiative - John Gerlt - Tab 9.V - Commentaries

Topic 4. Biomedically Important Targets

  1. What prioritization schemes have been used to select biomedically important targets to date? What are the unaddressed needs and opportunities for future biomedical target emphasis?
  2. What contributions can specifically biomedically selected targets for structural genomics projects make to the overall problem of understanding protein structure and function?
  3. How can partnerships between structural genomics centers and other researchers contribute to the solution of such structures?
  4. What has been the value of the biological themes of the current PSI Large Scale Centers?
  5. What are the most compelling biological themes for the future?

Speakers: Cheryl Arrowsmith, Wayne Anderson, TBN
References:
A Future for the Protein Structure Initiative - Edwards - Tab 9.V
Center for structural Genomics of Infectious Diseases - Tab 9.W - Other Useful Links
The Structural Genomics Consortium - Tab 9.W - Other Useful Links
The Cancer Genome Atlas - Tab 9.W - Other Useful Links

Topic 5. Challenging Problems - Systems, Complexes, Membrane Proteins

  1. What are the opportunities and obstacles to the application of a structural genomics approach to more complex systems?
  2. Are there advantages to all solving structures for a given metabolic pathway or signaling network or organelle?
  3. What progress has been made in the methods and setting up pipelines for determination of membrane protein structures and are these proteins now amenable to high-throughput structural approaches?
  4. Is the technology currently in place adaptable to the determination of these challenging structures? If not, what future technology developments are needed?
  5. Would an organized research network like the PSI be more efficient than more traditional approaches to these challenging problems?

 

Speakers: David Eisenberg, Wayne Hendrickson, Scott Lesley
References:
PSI Investigators' White Paper - Tab 7.
NIH Structural Biology Roadmap - Tab 9.W- Other Useful Links

Topic 6. Community Engagement - Targets, Service, Dissemination, Partnerships

  1. How can the biomedical research community broadly participate in the selection and prioritization of targets for high-throughput structure determination?
  2. How can the community make more effective use of the structures that are determined through structural genomics initiatives?
  3. What mechanisms exist for collaboration and/or partnerships between structural genomics research centers and individual investigators or groups of investigators (both structural biologists and non-structural biologists)?
  4. What other opportunities exist for coordinated structural biology research that can take advantage of the resources and infrastructure that have been created through the PSI.

Speakers: Mario Amzel, Dorothee Kern, Barry Gumbiner, Pamela Silver, Michael Snyder, Wesley Sundquist.
References:
PSI Investigators' White Paper - Tab 7.
PSI Knowledgebase Summary - Tab 9.H
PSI Materials Repository - Tab 9.I
PSI/Nature Knowledge Index - Nature Gateway - Tab 9.J
PSI Framework for Community Nominated Targets - Tab 9.M

Session V. Readback and Additional Discussion
 
  1. Have the previous discussions adequately captured the important issues, pros, cons, and options for the topics that were introduced?
  2. Are there other ideas for future structural genomics initiatives that have not been covered in the preceding sessions?
  3. What relative emphasis should be given to various potential goals of any future structural genomics initiatives?
Session VI. Program Prioritization and Structure
 
  1. Are the resources of PSI-2 optimally deployed for future work?
  2. What components are essential for any future organized structural genomics activity? Are these activities appropriately supported and run well?
  3. What components could be equally well supported through investigator-initiated, peer reviewed proposals or other mechanisms?
  4. What organizational and oversight structures are needed? Are the existing structures appropriate or should they be changed? If so, how?
  5. What is the appropriate scale of activity, given the current budget climate? How would this differ under various TBN budget scenarios that may develop in the coming years?

References:
Basic Administrative Information - Tab 8.
Reports of Annual Meeting and Advisory Committees - Tab 9. E, F, G, H, I
PSI Investigators' White Paper - Tab 7.
PSI Calendar of Meetings and Events - Tab 9.X