Report of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics: Fifth Round (2014)

THE NATIONAL ACADEMIES

Advisers to the Nation on Science, Engineering, and Medicine

National Academy of Sciences

National Academy of Engineering

Institute of Medicine

National Research Council

September 19, 2014

Jodi Swidzinski Hezky, Ph.D.

D. E. Shaw Research

120 West 45th Street, 39th Floor

New York, NY 10036

Dear Dr. Hezky:

This letter describes the work and transmits the final report of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Fifth Round.

The committee evaluated submissions received in response to a Request for Proposals (RFP) for Biomolecular Simulation Time on Anton, a supercomputer designed and built by D. E. Shaw Research (DESRES). Over the past four years (October 1, 2010 – September 30, 2014), DESRES has made an Anton system housed at the Pittsburgh Supercomputing Center (PSC) available to the noncommercial research community, based on the advice of previous National Research Council committees convened in 2010 – 2013. As in prior rounds, the goal of the fifth RFP for simulation time on Anton is to continue to facilitate breakthrough research in the study of biomolecular systems by providing a massively parallel system specially designed for molecular dynamics simulations. These capabilities allow multi-microsecond simulation timescales, which previously had been unobtainable. The program seeks to continue to support research that addresses important and high impact questions demonstrating a clear need for Anton’s special capabilities.

The success of the program has led DESRES to make the Anton machine housed at PSC available for an additional 3,300,000 node-hours over the period following October 2014, and DESRES has asked the National Research Council to once again facilitate the allocation of time to the non-commercial research community. The work of the National Research Council committee to evaluate proposals for time allocations was supported by a contract between D. E. Shaw Research and the National Academy of Sciences and was performed under the auspices of the National Research Council’s Board on Life Sciences.

To undertake this task, the National Research Council convened a committee of experts to evaluate the proposals submitted in response to the RFP. The committee of 16 was chaired by Dr. Angel Garcia, Department Head and Professor of Physics, and Senior Constellation Chaired Professor in Biocomputation and Bioinformatics at Rensselaer Polytechnic Institute. The committee members were selected for their expertise in molecular dynamics simulations and their experience in the subject areas represented in the 55 proposals that were considered by the committee. They comprised a cross section of the biomolecular dynamics field in academia, industry, and government including both senior and junior investigators.

The Anton RFP described the three criteria against which the committee was asked to evaluate proposals:

•   Scientific Merit, including the potential to advance understanding on an important problem or question in the field; potential for breakthrough science resulting in new discoveries and understanding; the impact that successful completion of the proposed research would have on knowledge, methods, and current barriers in the field; and a scientifically and technologically feasible project with clear, well-developed, and appropriate goals, objectives, and approach to the proposed studies.

•   Justification for Requested Time Allocation, including a clear and well-justified need for multi-microsecond simulation timescales and a clear and convincing justification that the length and number of proposed simulation runs and node-hours requested are necessary and sufficient to achieve the scientific objectives.

•   Investigator Qualifications and Past Accomplishments, including the appropriate experience and training to successfully conduct the proposed studies, evidence of knowledge and prior experience in molecular simulations, and past publications.

Proposals from investigators who had previously received an allocation of time on Anton were required to include progress reports. Following guidance provided by DESRES and PSC, the committee drew on these progress reports as supplemental material in its consideration of proposals. The committee also received information from PSC on the number of node-hours of simulation time remaining on 2013 Anton allocations.¹ As explained in the RFP, staff at PSC conducted an initial assessment of all proposal submissions for completeness and to determine whether they were technically feasible for simulation on Anton. A member of the PSC staff was present as an observer throughout the review committee’s discussions to address any additional questions that arose on Anton’s technical capabilities or on how the computer will be made available to researchers during the period of the project.

The committee was asked to identify proposals that best met the selection criteria defined above. As in the previous rounds of Anton time allocations, 100,000 node-hours was the maximum amount of time available to a proposal. Principal investigators could also request a lesser time allocation. The committee was further asked to allocate at least 25% of the time to principal investigators who had not previously received an Anton allocation. The judgments of the committee are based on which proposals best met the selection criteria described above and on the estimates of required simulation time provided by the applicants. The committee was permitted to consider a modified time allocation if it concluded that the proposed research required a greater or lesser number of node-hours than initially requested by an applicant.

Initial reviews of the proposals were provided by the 16 committee members. Each proposal was assigned a minimum of two primary reviewers who were asked to evaluate the proposal based on the RFP and guidelines described above. Review assignments were made so that proposals were not evaluated by reviewers from the applicant’s same institution or who had close collaborative relationships with an applicant.

________________

¹ This information was provided as of August 12, 2014. The committee was advised that approximately two months of simulation time remained on the 2013 round of allocations, and thus investigators who had not yet used their full allocation of simulation time may still be able to do so.

The committee held its meeting in Washington, D.C. on August 15, 2014. At the meeting, members undertook a detailed discussion of the proposals. The two primary reviewers were asked to summarize their review for the committee, which was followed by discussion of the proposed research. As described in detail above, committee members considered the scientific merit, justification of the requested time, and the qualifications of the principal investigator and key personnel. The committee then considered the slate of proposals, came to a consensus on which proposals it judged best met the selection criteria, and, in some cases, decided to suggest a modified allocation of time on Anton. Detailed comments for each of the 55 proposals are included in Appendix B. The committee has often included constructive suggestions for improvements in the research plans, which is of significant benefit to the broader community.

The committee concluded that the proposals listed below best met the selection criteria set forth in the RFP for Biomolecular Simulation Time on Anton. Of these 45 proposals, 18 proposals were selected for a modified allocation (identified below with an *).

In numerical order by proposal submission number, the proposals judged by the committee as best meeting the selection criteria of the RFP are:

PSCA14002P Mechanical Control of Kinesin’s ATPase Machinery; PI: Wonmuk Hwang, Texas A&M University [Returning user, identified for 50,000 node-hours]*

PSCA14003P Multi-Microsecond Simulations of A Model Two-Domain Protein; PI: Lillian Chong, University of Pittsburgh [Returning user, identified for 50,000 node-hours]

PSCA14004P The Roles of Protein Conformational Dynamics and Lipid Membrane Properties in the Function of Β-Barrel Assembly Machinery; PI: Karen Fleming, Johns Hopkins University [New user, identified for 100,000 node-hours]

PSCA14005P Roles of N-linked Glycans and GPI Anchor in Human Prion Protein Misfolding; PI: Wonpil Im, University of Kansas [Returning user, identified for 100,000 node-hours]

PSCA14006P Molecular Basis of G Protein-Biased Agonism at the Mu-Opioid Receptor; PI: Marta Filizola, Icahn School of Medicine at Mount Sinai [Returning user, identified for 100,000 node-hours]

PSCA14007P Investigation into the Coupling between Helix 6 Opening, RNA Binding and the Oligomeric State of the Lassa Virus Nucleoprotein; PI: Eric May, University of Connecticut [New user, identified for 50,000 node-hours]*

PSCA14008P Microsecond Simulations to Study Microbial Infection Mechanisms; PI: Jianing Li, University of Vermont [New user, identified for 50,000 node-hours]*

PSCA14010P Molecular Machinery Controlling Synaptic Vesicle Fusion; PI: Maria Bykhovskaia, Universidad Central del Caribe [Returning user, identified for 50,000 node-hours]*

PSCA14011P Dynamics of the Translational Machinery; PI: Zaida Luthey-Schulten, University of Illinois [Returning user, identified for 50,000 node-hours]

PSCA14012P The Molecular Determinants of Selective Ion Binding in the Sodium-Potassium Pump ATPase; PI: Benoît Roux, University of Chicago [Returning user, identified for 100,000 node-hours]

PSCA14013P The Structure of Peptide and Protein-induced Pores in Lipid Membranes; PI: Themis Lazaridis, City College of New York [Returning user, identified for 50,000 node-hours]*

PSCA14014P Sensing and Binding Mechanisms of Membrane Proteins; PI: Gregory Voth, University of Chicago [Returning user, identified for 84,000 node-hours]

PSCA14015P Self-assembly of Transmembrane Signaling Proteins; PI: Klaus Schulten, University of Illinois at Urbana-Champaign [Returning user, identified for 100,000 node-hours]

PSCA14016P Charting the Microscopic Pathway of DNA Branch Migration; PI: Aleksei Aksimentiev, University of Illinois at Urbana-Champaign [Returning user, identified for 100,000 node-hours]

PSCA14023P Mechanism of Allosteric Coupling in the Voltage-Sensing Phosphatase Ci-VSP; PI: Eduardo Perozo, University of Chicago [Returning user, identified for 50,000 node-hours]*

PSCA14025P MD Simulations of Interactions and Misfolding of Amyloid Beta (Aß) Proteins; PI: Yuri Lyubchenko, University of Nebraska Medical Center [New user, identified for 50,000 node-hours]*

PSCA14026P Substrate-Specific Allosteric Behavior in the Leucine Transporter from Analysis of Microsecond-Scale Molecular Dynamics Simulations; PI: Harel Weinstein, Weill Cornell Medical College of Cornell University [Returning user, identified for 91,000 node-hours]

PSCA14027P Molecular Determinants in Folding of Voltage-Gated Potassium Channel Kv1.3 Pore Helix; PI: Tobin Sosnick, University of Chicago [New user, identified for 50,000 node-hours]*

PSCA14030P Yeast Membrane Simulations with Inositol Phosphoceramide with Applications to Lateral Organization and binding of a Peripheral Membrane Protein; PI: Jeffery Klauda, University of Maryland [Returning user, identified for 100,000 node-hours]

PSCA14031P Characterizing the Disordered FG Repeat Domains of Nuclear Pore Complexes by Simulation and Experiment; PI: David Cowburn, Albert Einstein College of Medicine [Returning user, identified for 50,000 node-hours]*

PSCA14032P Glutamate Receptor Ligand Binding and Desensitization; PI: Albert Lau, Johns Hopkins University School of Medicine [Returning user, identified for 100,000 node-hours]

PSCA14033P Large-Scale Exploration of Sodium Channel Interactions with Small Molecules and Peptide Toxins; PI: Vladimir Yarov-Yarovoy, University of California, Davis [New user, identified for 100,000 node-hours]

PSCA14034P Formation and Breakdown of Peptide-Lipid Pores by the Antimicrobial Peptide Piscidin 1 in POPC/POPG Bilayers; PI: Richard Pastor, National Institutes of Health [New user, identified for 100,000 node-hours]

PSCA14035P Exploring Protein Core Plasticity and Rapid Ligand Access to Buried Binding Sites; PI: Rommie Amaro, University of California, San Diego [Returning user, identified for 100,000 node-hours]

PSCA14036P Revealing the Structural Basis of Functional Selectivity in GPCRs; PI: Ron Dror, Stanford University [New user, identified for 100,000 node-hours]

PSCA14037P The Conformational Rearrangement of Influenza Hemaggluinin: Molecular Details of the Initial Order-Disorder Transition; PI: Jose Onuchic, Rice University [Returning user, identified for 50,000 node-hours]*

PSCA14038P The Electron Transfer Rate in Ferredoxins; PI: Toshiko Ichiye, Georgetown University [New user, identified for 50,000 node-hours]

PSCA14039P Atomistic Modeling of the Resting and Activated States of the Human Hv1 Voltage-Gated Proton Channel; PI: Douglas Tobias, University of California, Irvine [Returning user, identified for 75,000 node-hours]*

PSCA14040P Structure, Conductance and Mechanism of Action of Calcium Channels Involved In Human Diseases; PI: Andrew Pohorille, University of California, San Francisco [Returning user, identified for 50,000 node-hours]

PSCA14041P Long Time Scale Molecular Dynamics Simulation of Protein Folding; PI: Martin Gruebele, University of Illinois at Urbana-Champaign [Returning user, identified for 100,000 node-hours]*

PSCA14042P Characterizing Conformational Dynamics of Sugar Transporters GLUT1 and XylE; PI: Emad Tajkhorshid, University of Illinois at Urbana-Champaign [Returning user, identified for 100,000 node-hours]

PSCA14043P Simulations of Protein Association and Transmembrane Peptides; PI: Matthias Buck, Case Western Reserve University [Returning user, identified for 50,000 node-hours]

PSCA14044P Determining the Mechanisms of Protein Folding in Membranes; PI: James Gumbart, Georgia Institute of Technology [Returning user, identified for 100,000 node-hours]

PSCA14045P Ligand-Specific Conformational Changes in CCR7 Coupled to Signaling Pathway Selection; PI: Dimitrios Morikis, University of California, Riverside [New user, identified for 100,000 node-hours]

PSCA14047P Functional Mechanism of a Bile Acid Transporter; PI: Fatemeh Khalili-Araghi, University of Illinois at Chicago [New user, identified for 43,000 node-hours]

PSCA14048P Real Time Exploration of Photosynthetic Light Harvesting Complex 2 (LH2) and Their Membrane Environments; PI: Seogjoo Jang, Queens College of the City University of New York [New user, identified for 60,000 node-hours]

PSCA14051P Beyond Active Site Catalysis: Determining the Role of Remote Mutations and Solvent in Substrate Recognition by Microsecond Molecular Dynamics; PI: Kendall Houk, University of California, Los Angeles [Returning user, identified for 100,000 node-hours]

PSCA14052P Microsecond Dynamics of HIV-1 Stem Loop1 RNA and A-Tract DNA for Computation of NMR Order Parameters and Comparison; PI: Ioan Andricioaei, University of California, Irvine [Returning user, identified for 50,000 node-hours]

PSCA14053P Evolution of Allosteric Signatures in GPCR; PI: Brian Dominy, Clemson University [New user, identified for 50,000 node-hours]*

PSCA14054P Receptor-Specific Distinction of Functional Mechanisms in G Protein Coupled Receptors; PI: Nagarajan Vaidehi, Beckman Research Institute at City of Hope Medical Center [Returning user, identified for 100,000 node-hours]

PSCA14057P Bacterial Membrane Selectivity in Antimicrobial Peptides; PI: Jeffrey Comer, Kansas State University [New user, identified for 50,000 node-hours]*

PSCA14058P Molecular Modeling Studies of Drug Binding to Human P-glycoprotein; PI: Alfredo Freites, University of California, Irvine [Returning user, identified for 75,000 node-hours]*

PSCA14059P The Role of Nascent Chain Tension in Modulating Codon Translation Rates; PI: Edward O'Brien, Pennsylvania State University [New user, identified for 75,000 node-hours]*

PSCA14062P The Role of Long-Range Interaction Formation in Determining Protein Topology at the Onset of Folding; PI: Jennifer Poutsma, Old Dominion University [New user, identified for 50,000 node-hours]*

PSCA14063P How Do Small-Molecule Interactions Alter the Conformational Landscape of Intrinsically Disordered P27?; PI: Chakra Chennubhotla, University of Pittsburgh [New user, identified for 50,000 node-hours]*

The time allocations for the 45 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 3,303,000 node-hours. Of the 45 proposals identified, 23 were identified at the approximately 100,000 node-hour level and 22 at the 50,000 node-hour level.² A total of approximately 1,128,000 node-hours were allocated to 17 proposals whose principal investigator did not receive time on Anton during the past four years (identified as “new users”). Approximately 34% of the available simulation time thus was allocated to new users of Anton. The remaining 2,175,000 node-hours are allocated to 28 proposals from investigators who had received allocations of time on Anton in previous rounds (identified as “returning users”).

In carrying out its task, the committee identified as many promising proposals as possible given the constraints on the total available simulation time.

The committee also wishes to raise two questions that arose during the proposal discussions. The first involves the restriction stated in the RFP that “each investigator can serve as a PI for only a single application for computer time on Anton.” It is common for proposals to include co-PIs and other key personnel in addition to the stated PI. The committee observed that it was also common for experts in molecular dynamics simulations to be associated with multiple proposals.³ The committee encourages D. E. Shaw Research and the Pittsburgh Supercomputing Center to consider whether additional guidance on the maximum number of proposals with which a senior investigator may be affiliated would add clarity to any future rounds of proposal solicitations.

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² The 100,000 node-hour level is defined as proposals that were identified for 70,000 node-hours or greater. The 50,000 node-hour level is defined as proposals that were identified for less than 70,000 node-hours.

³ With the intention solely of pointing to an example from among the current round of proposals, Professor Benoît Roux was listed as PI on one proposal and co-PI on two additional proposals. This type of situation was not unique to Professor Roux.

Finally, the committee encountered a request for simulation time awarded in the fourth round (2013-2014) to carry over into the fifth round of allocations (2014-2015). In this instance, the committee declined to recommend a time extension. However, the committee would like to note this request so that D. E. Shaw Research and the Pittsburgh Supercomputing Center can consider whether a policy on time extensions should be made.

The committee would like to thank D. E. Shaw Research, the Pittsburgh Supercomputing Center, and all of the 2014 Anton applicants for the opportunity to assist in identifying the proposals best meeting the selection criteria for time allocations on the Anton machine. The committee members were universally enthusiastic about the potential advances in the field that are facilitated by Anton and are looking forward to seeing the important new results from the Anton users.

Sincerely,

Angel Garcia
Chair

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Appendices:

A.   Table 1: Proposals Reviewed by the Committee

B.   Individual Proposal Summary Evaluations

C.   Proposal Evaluation Criteria

D.   Roster and Biographical Sketches of Committee Members

E.   The Board on Life Sciences, the Board on Chemical Sciences and Technology, and the National Academies

F.   Acknowledgment of Report Reviewer

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