Report of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics: Sixth Round (2015)

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Report of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Sixth Round Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Sixth Round Board on Life Sciences Board on Chemical Sciences and Technology Division on Earth and Life Studies 



September 28, 2015 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, Sixth 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 five years, DESRES has made an Anton system housed at the Pittsburgh Supercomputing Center (PSC) available to the non-commercial research community, based on the advice of previous National Research Council committees. As in prior rounds, the goal of the sixth 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. 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 2015, and DESRES asked the National Academies of Sciences, Engineering, and Medicine to once again facilitate the allocation of time to the non-commercial community. The work of the 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 Academies’ Board on Life Sciences. To undertake this task, the National Academies convened a committee of experts to evaluate the proposals submitted in response to the RFP. The committee of 22 was chaired by Dr. Robert Eisenberg, Bard Endowed Professor and Chairman Emeritus of the Department of Molecular Biophysics and Physiology at Rush University. The committee members were selected for their expertise in molecular dynamics simulations and experience in the subject areas represented in the 70 proposals that were considered. The members 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, which the committee drew on as supplemental material in its consideration of proposals. 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 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 22 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. The committee held its meeting in Washington, D.C. on August 4, 2015. At the meeting, the two primary reviewers were asked to summarize their reviews 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 considered the slate of proposals under consideration, 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 70 proposals are included in Appendix B. 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 48 proposals, 30 proposals were selected for a modified allocation (identified below with an *). 2 

In numerical order by proposal submission number, the proposals judged by the committee as best meeting the selection criteria of the RFP are: PSCA15002 McCammon, University of California, San Diego; MD simulation to elucidate activation pathway of TLR8 [Returning user, identified for 50,000 node-hours]* PSCA15003 Weinstein, Weill Cornell Medical College; Mechanistic differences in LeuT-fold transporter family proteins [Returning user, identified for 50,000 node-hours]* PSCA15005 Axelsen, University of Pennsylvania; Amyloid beta protein misfolding in reverse micelles [New user, identified for 25,000 node-hours]* PSCA15007 Tobias, University of California, Irvine; Modeling diffusion of membrane–bound signaling proteins on the microsecond timescale [Returning user, identified for 100,000 node- hours] PSCA15008 Li, University of Vermont; Mechanistic Study to Reveal How a Class B GPCR Responds to Hormone Signals [Returning user, identified for 50,000 node-hours]* PSCA15009 Im, University of Kansas; Influence of Glycosphingolipid Composition and Concentration on Lipid Clustering and Membrane Properties and Curvature [Returning user, identified for 100,000 node-hours] PSCA15018 Beratan, Duke University; Simulating the Electron Transfer Mechanisms of Extremophiles [Returning user, identified for 50,000 node-hours]* PSCA15020 Matyushov, Arizona State University; Anton Allocation: microsecond simulation of rate-limiting electron transfer in bacterial photosynthesis [Returning user, identified for 63,000 node-hours] PSCA15021 Lazaridis, City College of New York; The structure of peptide-induced pores in lipid membranes: Effects of lipid composition, molecularity, and peptide charge [Returning user, identified for 100,000 node-hours] PSCA15022 Scheraga, Cornell University; The effect of L- to D-amino acid racemization on the stability and protein dynamics of a beta-crystallin tetramer from the mammalian lens [Returning user, identified for 50,000 node-hours] PSCA15023 Loesche, Carnegie Mellon University; PTEN Signaling: Membrane Association as a Function of Protein Status [Returning user, identified for 100,000 node-hours] PSCA15025 Thirumalai, University of Maryland; Gateway for Phosphate Release from Myosin VI Nucleotide Binding Site [Returning user, identified for 75,000 node-hours] PSCA15026 Polenova, University of Delaware; Dynamic Characterization of the Spacer Peptide 1 in HIV-1 Capsid Protein Assemblies [New user, identified for 100,000 node-hours] PSCA15027 Weng, Whitehead Institute for Biomedical Research; Structural basis for enzyme catalytic promiscuity in plant specialized metabolism [New user, identified for 50,000 node-hours] 3 

PSCA15028 Gruebele, University of Illinois at Urbana-Champaign; Testing the mechanistic convergence of protein folding experiments and simulations [Returning user, identified for 75,000 node-hours]* PSCA15029 van der Vliet, University of Vermont; Structure/Function Relationships of the Redox- Regulation of the Src Kinase [New user, identified for 50,000 node-hours]* PSCA15030 Pohorille, University of California San Francisco; Toward rational design of antiviral drugs: linking structure and electrophysiology of viral ion channels [Returning user, identified for 50,000 node-hours] PSCA15032 O'Brien, Pennsylvania State University; Co-translational protein folding on the ribosome: Pathways, interactions and translation rates [Returning user, identified for 50,000 node-hours]* PSCA15034 Ulmschneider, Johns Hopkins University; Membrane assembly and the equilibrium configurational ensemble of antimicrobial peptide channels [New user, identified for 75,000 node- hours]* PSCA15035 Ackad, Southern Illinois University, Edwardsville; Determining the Motion of a Molecular Nano Bio-Switch [New user, identified for 50,000 node-hours]* PSCA15036 Aksimentiev, University of Illinois at Urbana-Champaign; Molecular basis of epigenetic regulation [Returning user, identified for 100,000 node-hours] PSCA15038 Cisneros, Wayne State University; Molecular dynamics investigation of hen egg white lysozyme folding/unfolding for enabling mass spectrometry interpretation [New user, identified for 50,000 node-hours] PSCA15039 Roux, University of Chicago; Proton traffic in the sodium-potassium pump ATPase [Returning user, identified for 60,000 node-hours]* PSCA15041 Garcia, Rensselaer Polytechnic Institute; Comparing the Role of Arginine and Lysine Sidechains in Antimicrobial Peptide Activity [Returning user, identified for 100,000 node-hours] PSCA15043 Klauda, University of Maryland; Phase Separation of Long-chained Inositol Phosphoceramide in Model Yeast Membranes [Returning user, identified for 100,000 node-hours] PSCA15044 Pastor, NHLBI, National Institutes of Health; A 25 μs Trajectory of Alamethicin in a DOPC Bilayer [Returning user, identified for 100,000 node-hours]* PSCA15046 Bahar, University of Pittsburgh; Microsecond molecular dynamics guided by elastic network model: Application to AMPA receptor druggability [Returning user, identified for 75,000 node-hours]* PSCA15047 Cowburn, Albert Einstein College of Medicine; Characterizing the disordered FG repeat domains of Nuclear Pore Complexes by simulation and experiment [Returning user, identified for 50,000 node-hours]* 4 

PSCA15050 Lyman, University of Delaware; Compositional Complexity: Packing, Lateral Structure, and Nanoscale Dynamics in Plasma Membrane Mixtures [Returning user, identified for 100,000 node-hours] PSCA15051 Buck, Case Western Reserve University; Simulations of TM helix dimers and GTPase lipid interactions [Returning user, identified for 50,000 node-hours] PSCA15052 Luthey-Schulten, University of Illinois at Urbana-Champaign; Dynamics of the Translational Machinery [Returning user, identified for 50,000 node-hours] PSCA15053 Dror, Stanford University; Structural basis for protein-ligand-mediated, constitutive, and biased signaling in chemokine GPCRs [Returning user, identified for 100,000 node-hours] PSCA15056 Shukla, University of Illinois at Urbana-Champaign; Ligand-Binding Pathways in a Glutamate Receptor [New user, identified for 100,000 node-hours] PSCA15057 Sosnick, University of Chicago; Molecular Determinants of Folding of Potassium Channel [Returning user, identified for 60,000 node-hours]* PSCA15058 Post, Purdue University; The Effect of Tyr130 Phosphorylation on the Structure, Dynamics and Binding Energetics of the SYK tandem SH2 Protein [Returning user, identified for 50,000 node-hours]* PSCA15059 Haddadian, University of Chicago; Modeling the Amyloid-β fibril formation on 2D surfaces using self-assembled-monolayers (SAM) [New user, identified for 50,000 node-hours]* PSCA15060 Palczewski, Case Western Reserve University; Mechanism of biased signaling in serotonin receptors [Returning user, identified for 100,000 node-hours] PSCA15061 Onuchic, Rice University; The Conformational Rearrangement of Influenza Hemagglutinin: Molecular Details of the Transition [Returning user, identified for 100,000 node- hours] PSCA15066 Schulten, University of Illinois at Urbana-Champaign; A Computational Study for Understanding Structure and Dynamics in Circular Proteins [Returning user, identified for 75,000 node-hours]* PSCA15071 Freites, University of California, Irvine; Molecular modeling studies of eye lens proteins at physiological concentrations [Returning user, identified for 50,000 node-hours]* PSCA15072 Grant, University of Michigan; G protein activation mechanisms [New user, identified for 50,000 node-hours] PSCA15073 Perozo, University of Chicago; Coupled movements between the voltage-sensing and the phosphatase domains of Ci-VSP [Returning user, identified for 60,000 node-hours]* PSCA15074 Tombola, University of California, Irvine; Atomistic modeling of the human Hv1 voltage-gated proton channel [New user, identified for 50,000 node-hours]* 5 

PSCA15075 Sotomayor, Ohio State University; Bending and Refolding of an Atypical Cadherin Fragment Involved in Inner Ear Mechanotransduction [New user, identified for 100,000 node- hours] PSCA15077 Yarov-Yarovoi, University of California, Davis; Large-scale exploration of sodium channel interactions with small molecules and peptide toxins [Returning user, identified for 70,000 node-hours]* PSCA15078 Agard, University of California San Francisco; Conformational Dynamics of the Molecular Chaperone Heat Shock Protein 90 (HSP90) [New user, identified for 74,000 node- hours]* PSCA15079 Jang, Queens College of the City University of New York; Exploration of stability and quasistatic disorder of in silico models for mutant and synthetic analogues of photosynthetic light harvesting 2 (LH2) complex through microsecond molecular dynamics simulation [Returning user, identified for 20,000 node-hours]* PSCA15080 Kurnikova, Carnegie Mellon University; Simulating Gating in Glutamate Receptors [Returning user, identified for 100,000 node-hours] The time allocations for the 48 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 3,357,000 node-hours. Of the 48 proposals identified, 24 were identified at the approximately 100,000 node-hour level and 24 at the 50,000 node-hour level or below.1 A total of approximately 824,000 node-hours were allocated to proposals whose principal investigator did not receive time on Anton during the past five years (identified as “new users”). Approximately 25% of the available simulation time thus was allocated to new users of Anton. The remaining 2,533,000 node-hours are allocated to 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 total simulation time requested by the submitted proposals was over 6 million node hours. As a result, a number of interesting proposals were not able to be recommended in this round, entailing difficult decisions. The committee would like to thank D. E. Shaw Research, the Pittsburgh Supercomputing Center, and all of the 2015 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, Robert Eisenberg Chair cc: Dr. Markus Dittrich, Pittsburgh Supercomputing Center Dr. Gregory Symmes, National Academies of Sciences, Engineering, and Medicine Dr. Frances Sharples, National Academies of Sciences, Engineering, and Medicine 1 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. 6 

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 Academies F. Acknowledgment of Report Reviewer 7 

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