Summary

This document describes the work and transmits the decisions of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Fourteenth 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 13 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 (the National Academies). As in those prior rounds, the goal of the fourteenth 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 for 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 2023, and DESRES asked the National Academies 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 selection committee of experts to evaluate the proposals submitted in response to the RFP. The committee of 22 was chaired by Jeffrey Skolnick, Regent’s Professor in the School of Biological Sciences at the Georgia Institute of Technology. The committee members were selected for their expertise in MD simulations and experience in the subject areas represented in the 59 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 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.
• 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.

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’s time allocations of 460,000 MDUs was the maximum amount of time available to a proposal. Principal investigators (PIs) could also request a smaller time allocation. The committee was permitted, at its discretion, to consider a modified time allocation than otherwise requested. The committee was further asked to target, to the extent possible, at least 25% of allotted time to PIs 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.

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 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 or personal relationships with an applicant. These conflicts of interest (COIs) are included in Appendix H.

The committee held its final meeting on September 1, 2023, in a hybrid fashion, with some committee members attending in person in Washington, DC, and others joining virtually. 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. 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 (if virtual) or left the room (if in person) 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 PI and key personnel. The committee reviewed the slate of proposals under consideration and selected 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 59 proposals are included in Appendix B.

The committee judged the proposals listed below best met the selection criteria set forth in the RFP for Biomolecular Simulation Time on Anton 2. Of these 46 proposals, 23 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:

BIO100005P Carol Post, Purdue University; Decoding Large-Scale Conformational Transitions in Non-Receptor Tyrosine Kinases [Returning user identified for 459,436 MDUs]

IBN130013P Maria Bykhovskaia, Wayne State University; Protein Machinery Regulating Synaptic Vesicle Fusion [Returning user identified for 300,000 MDUs]*

MCB100016P Aleksei Aksimentiev, University of Illinois at Urbana-Champaign; Single-stranded DNA force field for precision nanopore sequencing [Returning user identified for 429,199 MDUs]

MCB100018P Benoit Roux, University of Chicago; Luminal Gate of the ATP-driven calcium pump SERCA [Returning user identified for 460,000 MDUs]

MCB100024P Martin Gruebele, University of Illinois at Urbana-Champaign; Characterizing protein complexes in-cell [Returning user identified for 460,000 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 300,000 MDUs]*

MCB110012P Jeffery Klauda, University of Maryland at College Park; Lipid mediated EmrE protein-ligand binding pathway and dimerization of EmrE [Returning user identified for 300,000 MDUs]*

MCB110023P Matthias Buck, Case Western Reserve University; Eph receptor domain - membrane interactions [Returning user identified for 130,000 MDUs]*

MCB110066P Edward Lyman, University of Delaware; Coupling lipid asymmetry and GPCR function [Returning user identified for 460,000 MDUs]

MCB130052P Themis Lazaridis, City University of New York; Mechanism of membrane remodeling by the caveolin 8S complex [Returning user identified for 300,000 MDUs]*

MCB130061P Eduardo Perozo, University of Chicago; Understanding the Voltage-Dependent Conformational Changes Underlying Prestin Electromotility [Returning user identified for 460,000 MDUs]

MCB140052P Richard Pastor, National Institutes of Health; Effects of lipid asymmetry and cholesterol on the mechanism of antimicrobial peptides [Returning user identified for 460,000 MDUs]

MCB150024P Marcos Sotomayor, The Ohio State University; In-Silico Electrophysiology of Experimentally Supported AlphaFold 2 Models of the Vertebrate Inner-Ear Mechanotransduction Apparatus [Returning user identified for 460,000 MDUs]

MCB160079P Sharon Loverde, City University of New York; Probing the Unwrapping Pathway of the Nucleosome Core Particle Using Free Energy Calculations [Returning user identified for 460,000 MDUs]

MCB160089P Igor Vorobyov, University of California, Davis; Molecular dynamics simulations to assess state-specific multi-target interactions of hERG channel blockers [Returning user identified for 456,000 MDUs]

MCB180080P Ira Kurtz, University of California, Los Angeles; Lipid mediation of the inter-domain contacts between the cytoplasmic and transmembrane domains in SLC4 proteins [Returning user identified for 454,950 MDUs]

MCB180086P Gaurav Arya, Duke University; Conformational Transitions of the ATPasepRNA Ring during DNA Packaging in Φ29 [Returning user identified for 266,088 MDUs]

MCB190052P Jianhan Chen, University of Massachusetts at Amherst; Activation of BK and TPPV4 Channels [Returning user identified for 150,000 MDUs]*

MCB190063P James Berger, Johns Hopkins University; ATP-Dependent Allosteric Coordination in Type IIA Topoisomerases [Returning user identified for 460,000 MDUs]

MCB190076P Alexander Sodt, National Institutes of Health; Predicting how small changes in sterol chemical structure affect membrane fusion and fission [Returning user identified for 460,000 MDUs]

MCB200078P Rui Sun, University of Hawaii at Manoa; Investigate Paracellular Permeation of Small Molecules through Tight Junctions [Returning user identified for 250,000 MDUs]*

MCB200085P Jing Li, University of Mississippi; Elucidating the modulation mechanisms of PUFAs on the ASIC3 channel [Returning user identified for 348,000 MDUs]*

MCB200087P Paul Robustelli, Dartmouth College; Understanding the effects of 1,6-hexanediol on the properties of biomolecular condensates [Returning user identified for 460,000 MDUs]

MCB200093P Viviana Monje-Galvan, State University of New York at Buffalo; Protein-lipid Interactions in Membrane Permeabilization [Returning user identified for 345,000 MDUs]*

MCB210005P Giulia Palermo, University of California, Riverside; Establishing the molecular determinants of off-target tolerance and trans-cleavage activity of CRISPR-Cas12a [Returning user identified for 460,000 MDUs]

MCB210009P Alemayehu Gorfe, University of Texas Health Sciences Center at Houston; Dynamics of lipid-anchored small GTPases [Returning user identified for 460,000 MDUs]

MCB210010P Thomas Szyperski, State University of New York at Buffalo; Simulation of the - 10 Oc Cold State of 4-Helix Bundle Dcub1 Featuring a Large Water Core [Returning user identified for 230,000 MDUs]*

MCB210014P Nipavan Chiamvimonvat, University of California, Davis; Regulation of cardiac small-conductance calcium-activated potassium channel [Returning user identified for 300,000 MDUs]*

MCB210015P Susan Marqusee, University of California, Berkeley; Mechanisms of cooperative crosstalk in GPCR dimers [Returning user identified for 345,000 MDUs]*

MCB210016P Jessica Swanson, University of Utah; Engineering Methanotrophs for Efficient Methane Removal from Air [Returning user identified for 150,000 MDUs]*

MCB220008P Jin Yu, University of California, Irvine; Interrogating transcription factor and enzyme translocational motions along DNA/RNA employing all-atom computational microscope [Returning user identified for 220,000 MDUs]

MCB220010P Gaetano Montelione, Rensselaer Polytechnic Institute; Structural Dynamics of Integral Membrane Proteins Mediating Drug Transport [Returning user identified for 400,000 MDUs]*

MCB220011P Juan Vanegas, Oregon State University; Membrane-Mediated and Chemical Activation of G-Protein Coupled Receptors [Returning user identified for 460,000 MDUs]

MCB230000P Jie Xiao, Johns Hopkins University; Conformational Dynamics and Allosteric Activation Mechanism of the Core Bacterial Septal Cell Wall Synthesis Complex [New user identified for 305,000 MDUs]*

MCB230001P Surl Hee Ahn, University of California, Davis; Unveiling the mechanism of alpha-synuclein aggregation and prevention with small molecules using molecular dynamics [New user identified for 335,000 MDUs]*

MCB230002P Anum Glasgow, Columbia University; Reshaping the free energy landscape of phosphofructokinase-1 by allosteric regulation [New user identified for 330,000 MDUs]*

MCB230003P John Cannon, University of Missouri; Anti-CD3 antibodies activate TCR by lipid exchange [New user identified for 150,000 MDUs]*

MCB230004P Linda Columbus, University of Virginia; Conformational dependent lipid recruitment in LeuT: Identifying the mechanisms of lipid selectivity and binding [New user identified for 404,400 MDUs]

MCB230007P Arek Kulczyk, Rutgers University; Hybrid methods for combined experimental and computational examination of laminin structure and dynamics with implications for human disease. [New user identified for 200,000 MDUs]*

MCB230009P Alex Pak, Colorado School of Mines; Conformational Switches for Bacterial Surface Layer Protein Assembly [New user identified for 303,000 MDUs]

MCB230010P M. Madan Babu, St. Jude Children’s Research Hospital; Explaining the molecular origins of β2 adrenergic receptor pharmacology through molecular dynamics simulations [New user identified for 305,000 MDUs]*

MCB230012P Brittany Morgan, University of Notre Dame; Rationalizing Differences in the Reactivity and Site Selectivity of Covalent Ligands that Bind the Flexible, Multi-Domain heterogenous nuclear RiboNucleoProteins (hnRNPs) H and F [New user identified for 460,000 MDUs]

MCB230013P Joseph Mindell, National Institutes of Health; Mechanism of ClC-7 transporter inhibition by phosphoinositides [New user identified for 305,000 MDUs]*

MCB230014P Peter Olmsted, Georgetown University; Permeation of Actives in the Stratum Corneum Lipid Matrix [New user identified for 280,000 MDUs]

MCB230019P Andriy Anishkin, University of Maryland at College Park; Ionic Conductance, Metabolite Permeability and Lipid-Transporting function of the Bacterial Mechanosensitive channel MscS [New user identified for 265,000 MDUs]*

MCB230020P Arvind Ramanathan, Argonne National Lab; Mechanistic underpinnings of antibody-glycoprotein complex formation of emerging pandemic potential viruses for vaccine development [New user identified for 400,000 MDUs]*

The time allocations for the 46 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 15,800,000 MDUs. Approximately 25.6% of MDUs were allocated to 13 proposals whose PIs have not received time on Anton or Anton 2 (identified as “new users”). Approximately 74.4% of the MDUs were allocated to proposals from PIs 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 number of allocations recommended given the constraints on the total available simulation time. The total simulation time requested by the submitted proposals was more than 24,398,000 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 the 2023 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 are 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.