November 5, 2021
Jodi 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, Twelfth Round.
The committee evaluated submissions received in response to a Request for Proposals (RFP) for Biomolecular Simulation Time on Anton 2, a supercomputer designed and built by D. E. Shaw Research (DESRES). Over the past 11 years, DESRES has made an Anton or Anton 2 system housed at the Pittsburgh Supercomputing Center (PSC) available to the non-commercial research community, based on the advice of previous committees of the National Academies of Sciences, Engineering, and Medicine. As in those prior rounds, the goal of the twelfth RFP for simulation time on Anton 2 is to continue to facilitate breakthrough research in the study of biomolecular systems by providing a massively parallel system specially designed for molecular dynamics (MD) 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 2 machine housed at PSC available for approximately 15,800,000 molecular dynamic units (MDUs) over the period following November 2021, and DESRES asked the National Academies of Sciences, Engineering, and Medicine to 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 DESRES and the National Academy of Sciences and was performed under the auspices of the National 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 20 was chaired by James C. “J.C.” Gumbart, Associate Professor at the Georgia Institute of Technology. The committee members were selected for their expertise in molecular dynamics simulations and experience in the subject areas represented in the 49 proposals that were considered. The members comprised a cross-section of the biomolecular dynamics field in academia, including both senior and junior investigators.
The Anton 2 RFP described the three criteria against which the committee was asked to evaluate proposals:
- Level of Scientific Merit, including the potential to advance understanding on an important problem or question in the field; the potential for breakthrough science
- Justification for Requested Time Allocation, including 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.
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 approaches to the proposed studies.
Proposals from investigators who had previously received an allocation of time on Anton or Anton 2 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 if they were technically feasible for simulation on Anton 2. A member of the PSC staff was present as an observer throughout the committee’s discussions to address any additional questions that arose on Anton 2’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. Anton 2 time allocation of 460,000 MDUs was the maximum amount of time available to a proposal. Principal investigators could also request a smaller 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 smaller number of node-hours than initially requested by an applicant, up to the 460,000 MDUs maximum.
Initial reviews of the proposals were provided by the 20 committee members. Each proposal was assigned a minimum of two primary reviewers who were asked to evaluate the proposal based on the RFP and the 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. These conflicts of interest (COIs) are included in Appendix H.
The committee held its virtual meetings on September 8–10, 2021. At the meetings, the two primary reviewers were asked to summarize their reviews for the committee, which was followed by discussion of the proposed research. Committee members determined to have a COI with a proposal were excused from the committee discussion on that proposal and placed in a virtual waiting room until discussion of the proposal was complete. 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 reviewed 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 2. Detailed comments for each of the 49 proposals are included in Appendix B1.
___________________
1 These appendices are not available to the public.
The committee concluded that the proposals listed below best met the selection criteria set forth in the RFP for Biomolecular Simulation Time on Anton 2. Of these 47 proposals, 19 proposals were selected for a modified allocation (identified below with an *).
In alphabetical and numerical order by proposal submission number, the proposals judged by the committee as best meeting the selection criteria of the RFP are:
CHE100024P Kendall Houk, University of California, Los Angeles; Mechanistic Study and Catalytic Site Redesign of Pyr Family of Enzymes to Access Potent Antibiotics [Returning user identified for 443,808 MDUs]
CHE120043P Gregory A. Voth, The University of Chicago; Molecular Mechanisms of SARSCoV-2 Spike Protein Binding and HIV-1 Gag Matrix Reorganization [Returning user identified for 180,000 MDUs]*
IBN130013P Maria Bykhovskaia, Wayne State University; Protein Machinery Regulating Synaptic Vesicle Fusion [Returning user identified for 230,000 MDUs]*
MCB100016P Aleksei Aksimentiev, University of Illinois at Urbana-Champaign; Condensation Versus ATP: The Microscopic Mechanism of a Biological Hydrotrope [Returning user identified for 447,911 MDUs]
MCB100017P Emad Tajkhorshid, University of Illinois at Urbana-Champaign; Conformational Dynamics of ABCG2 Transporter Regulated by Nucleotide and Drug Binding [Returning user identified for 446,029 MDUs]
MCB100018P Benoit Roux, Loyola University of Chicago; Binding Specificity of Inhibitors and Conformational Dynamics in Abl- and Src-Kinases [Returning user identified for 230,000 MDUs]*
MCB100019P Wonmuk Hwang, Texas A&M University; Structural Basis for the Kinesin Motor Binding and Diffusing on the Microtubule Surface [Returning user identified for 460,000 MDUs]
MCB100024P Martin Gruebele, University of Illinois at Urbana-Champaign; Dynamics of Intrinsically Disordered Proteins in the Cytoplasm: Probe for a New Generation Force Field [Returning user identified for 230,000 MDUs]*
MCB110005P Douglas James Tobias, University of California, Irvine; Atomistic Modeling of Cooperativity in the Activation of the Hv1 Proton Channel and the Regulation of Aquaporin 0 Water Permeability [Returning user identified for 460,000 MDUs]
MCB110012P Jeffery B. Klauda, University of Maryland at College Park; Studies of Transmembrane Proteins: PlexinA1 Intracellular Dimerization and Toxin Deactivation of 5-HT3 [Returning user identified for 230,000 MDUs]*
MCB110023P Matthias Buck, Case Western Reserve University; Plexin and Eph Receptor Domain–Membrane Interactions [Returning user identified for 155,000 MDUs]*
MCB110059P Wonpil Im, Lehigh University; Interactions of Human DGAT1 with Acyl-CoA and Diacylglycerols [Returning user identified for 139,000 MDUs]*
MCB120085P Maria Kurnikova, Carnegie Mellon University; Sub-conducting States of Ionotropic Glutamate Receptors [Returning user identified for 230,000 MDUs]*
MCB130045P Albert Lau, Johns Hopkins University; Mechanism of Action of an NMDA Receptor Functional Antibody [Returning user identified for 460,000 MDUs]
MCB130052P Themis Lazaridis, City University of New York; Understanding the Target Selectivity of Antimicrobial & Pore-Forming Peptides [Returning user identified for 230,000 MDUs]*
MCB130061P Eduardo Perozo, The University of Chicago; The Role of Lipid-Protein Interactions in the Gating Mechanism of Mechanosensitive Channels [Returning user identified for 460,000 MDUs]
MCB140052P Richard W. Pastor, National Institutes of Health; Initiation and Evolution of Pores Formed by Influenza Fusion Peptides [Returning user identified for 459,400 MDUs]
MCB140059P Eric May, University of Connecticut; Atomistic Curvature-Based Lipid Segregation in Cardiolipin Containing Bilayers [Returning user identified for 460,000 MDUs]
MCB140062P Vladimir Yarov-Yarovoy, University of California, Davis; Multi-Microsecond Simulations of TRPV1 Channel Modulation by Small Molecules and Peptides [Returning user identified for 230,000 MDUs]*
MCB140063P Yuri Lyubchenko, University of Nebraska Medical Center; Role of Lipid Bilayers in the Dynamics and Misfolding of Alpha-Synuclein Protein [Returning user identified for 230,000 MDUs]*
MCB150024P Marcos Sotomayor, The Ohio State University; In-Silico Electrophysiology of the Inner-Ear Hair-Cell Mechanotransduction Channel TMC1 [Returning user identified for 455,779 MDUs]
MCB160087P Mahmoud Moradi, University of Arkansas at Little Rock; Characterizing pH-Triggered Activation of Influenza Hemagglutinin Protein [Returning user identified for 420,000 MDUs]
MCB160089P Igor Vorobyov; University of California, Davis; Elucidating Molecular Determinants of Pro-Arrhythmic Proclivities of Beta Blocking Drugs for a Multi-Scale Modeling Pipeline [Returning user identified for 230,000 MDUs]*
MCB170100P Janice Robertson, Washington University; Cardiolipin Modulation of Transporter Dimerization in Membranes [Returning user identified for 460,000 MDUs]
MCB180081P Liqun Zhang, Tennessee Technological University; Anton Simulation on Human Beta Defensins Binding with and Disruption Inside Lipid Membranes [Returning user identified for 139,000 MDUs]*
MCB180091P William Goddard, California Institute of Technology; Structures and Mechanism for G-Protein and Beta-Arrestin Signaling of GPCRs Through MD Simulations [Returning user identified for 276,000 MDUs]*
MCB190044P Jerome Lacroix, Western University of Health Sciences; Generating an Inactivated State Model for the Mechanosensitive Channel Piezo1 [Returning user identified for 460,000 MDUs]
MCB190052P Jianhan Chen, University of Massachusetts Amherst; Voltage Gating of TMEM16A and BK Channels [Returning user identified for 440,000 MDUs]
MCB200071P Denise Okafor, The Pennsylvania State University; Mechanisms of Ligand Regulation in the FXR-RXR Nuclear Receptor Heterodimer [Returning user identified for 434,730 MDUs]
MCB200078P Rui Sun, University of Hawaii at Mānoa; Characterizing the Properties of Exosomes for Next-Generation Drug Delivery Systems [Returning user identified for 421,248 MDUs]
MCB200085P Jing Li, University of Mississippi; Structural Impacts of Disease-Associated Mutations on the Activation of a Human Cardiac Nav Channel [Returning user identified for 460,000 MDUs]
MCB200087P Paul Robustelli, Dartmouth College; Characterizing the Binding Mechanisms of Castration-Resistant Prostate Cancer Therapeutics to the Intrinsically Disordered N-Terminal Domain of the Androgen Receptor [Returning user identified for 460,000 MDUs]
MCB200095P Taras Pogorelov, University of Illinois at Urbana-Champaign; Signaling Protein Dynamics in Mammalian Cytoplasm [Returning user identified for 230,000 MDUs]*
MCB210004P Aaron Dinner, The University of Chicago; Dynamical Analysis of the Voltage-Sensing Domain in Ci-VSP [New user identified for 230,000 MDUs]*
MCB210005P Giulia Palermo, University of California, Riverside; Deciphering the Mechanism of Increased Gene Editing Specificity in Emerging Variants of the CRISPR-Cas9 System [New user identified for 460,000 MDUs]
MCB210008P Rejwan Ali, Icahn School of Medicine at Mount Sinai; Micro-Second Scale Molecular Dynamics Simulations of Neurokinin 1 Receptor in Anton2 Supercomputer [New user identified for 141,000 MDUs]*
MCB210009P Alemayehu Gorfe, University of Texas Health Science Center at Houston; Dynamics of Lipid-Anchored Small GTPases [Returning user identified for 460,000 MDUs]
MCB210010P Thomas Szyperski, SUNY at Buffalo; Protein Core Water Penetration at the Onset of Cold Denaturation [New user identified for 300,730 MDUs]
MCB210012P Gabriel Lander, The Scripps Research Institute; Investigating the Dynamics Underpinning Proteolysis in the Mitochondrial Protease LONP1 [New user identified for 460,000 MDUs]
MCB210013P Alessio Accardi, Weill Cornell Medical College; Molecular Mechanisms of Common Gate Activation and H+:Cl- Exchange in the CLC-ec1 Transporter [New user identified for 460,000 MDUs]
MCB210014P Nipavan Chiamvimonvat, University of California, Davis; Regulation of Cardiac Small-Conductance Calcium-Activated Potassium Channel [New user identified for 429,675 MDUs]
MCB210015P Susan Marqusee, University of California, Berkeley; Uncovering Determinants for Ligand Sensitivity and Potency in a Subfamily of Closely Related GPCRs [New user identified for 460,000 MDUs]
MCB210016P Jessica Swanson, The University of Utah; Association Driven Transformations: Protein Targeting to Lipid Droplets and ATP-Driven Translocation [New user identified for 240,810 MDUs]
MCB210017P Patricia Reggio, University of North Carolina Greensboro; Phyto- and EndoCannabinoid Interaction at the Ionotropic Cannabinoid Receptor TRPV1 [Returning user identified for 230,000 MDUs]*
MCB210018P Henry Woodcock, University of South Florida; Elucidating the Conformational Dynamics of the Antimicrobial Target 1-Deoxy-D-Xylulose 5-Phosphate Synthase in Atomic Resolution [New user identified for 300,000 MDUs]
MCB210020P Michael Regnier, University of Washington; Dynamics of Super Relaxed Myosin and Modulation by 2′-Deoxy-ATP [New user identified for 230,000 MDUs]
MCB210021P Sandhya Kortagere, Drexel University; Distinct Conformational States Induced by Agonists Promote Biased Signaling at the Dopamine D3 Receptors [New user identified for 100,000 MDUs]*
The time allocations for the 47 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 15,800,000 MDUs. Approximately 24.1% of MDUs were allocated to proposals whose principal investigators have not received time on Anton or Anton 2 (identified as “new users”). Approximately 75.9% of the MDUs were allocated to proposals from principal investigators who have received allocations of time on Anton 2 in previous rounds (identified as “returning users”).
In carrying out its task, the committee identified as many promising proposals as possible and made difficult decisions on the amount of allocations recommended given the constraints on the total available simulation time. The total simulation time requested by the submitted proposals was more than 20,879,000 MDUs. As a result, not every proposal could be recommended for an allocation and many interesting projects received recommendations for less than the full allocation amount.
The committee would like to thank DESRES, PSC, and all of the 2021 Anton 2 applicants for the opportunity to assist in identifying the proposals best meeting the selection criteria for time allocations on the Anton 2 machine. The committee members were universally enthusiastic about the potential advances in the field that are facilitated by Anton 2 and are looking forward to seeing the important new results from the Anton 2 users.
Sincerely,
J.C. Gumbart
Chair, Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Twelfth Round
cc: Dr. Philip Blood, Pittsburgh Supercomputing Center
Dr. Elizabeth Eide, National Academies of Sciences, Engineering, and Medicine
Dr. Kavita Berger, National Academies of Sciences, Engineering, and Medicine
