Report of the Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics: Thirteenth Round (2022)

October 28, 2022

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, Thirteenth 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 12 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 thirteenth 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 2022, 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 committee of experts to evaluate the proposals submitted in response to the RFP. The committee of 20 was chaired by Carol B. Post, Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at Purdue University. The committee members were selected for their expertise in MD simulations and experience in the subject areas represented in the 51 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 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 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. 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 maximum 460,000 MDUs.

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 meeting on August 26, 2022, 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, 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 51 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 2. Of these 44 proposals, 12 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:

IBN130013P Maria Bykhovskaia, Wayne State University; Protein Machinery Regulating Synaptic Vesicle Fusion [Returning user identified for 206,795 MDUs]*

MCB100016P Aleksei Aksimentiev, University of Illinois at Urbana-Champaign; Precision Sequencing of RNA Using a Biological Nanopore [Returning user identified for 460,000 MDUs]

MCB100017P Emad Tajkhorshid, University of Illinois at Urbana-Champaign; Conformational Dynamics of Influenza Hemagglutinin Leading to Its Membrane Fusion [Returning user identified for 421,250 MDUs]

MCB100018P Benoit Roux, University of Chicago; C-Type Inactivation in a Voltage-Gated Potassium Channel [Returning user identified for 460,000 MDUs]

MCB100019P Wonmuk Hwang, Texas A&M University; Position-Dependent Interactions Between the Kinesin Motor and the Microtubule Track [Returning user identified for 460,000 MDUs]

MCB100024P Martin Gruebele, University of Illinois at Urbana-Champaign; Seeing Order in Chaos: Deconstructing Hetero-Oligomeric Protein Assembly in the Crowded 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 460,000 MDUs]

MCB110059P Wonpil Im, Lehigh University; Molecular Mechanism of Antifolate Binding and Anion Exchange by Human RFC [Returning user identified for 460,000 MDUs]

MCB120085P Maria Kurnikova, Carnegie Mellon University; Structural Features of Subconducting States of Ionotropic Glutamate Receptors [Returning user identified for 460,000 MDUs]

MCB140052P Richard W. Pastor, National Institutes of Health; Lipid Binding and Displacement by ApoB-100 [Returning user identified for 460,000 MDUs]

MCB140063P Yuri Lyubchenko, University of Nebraska Medical Center; Self-Assembly of Amyloid Beta and Alpha-Synuclein in Presence of Membranes [Returning user identified for 460,000 MDUs]

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

MCB160079P Sharon Loverde, City University of New York; Oncogenic Effects on the Structure and Stability of the Nucleosome Core Particle [Returning user identified for 392,170 MDUs]

MCB160087P Mahmoud Moradi, University of Arkansas at Little Rock; Conformational Dynamics of YidC Insertase in Gram-Positive and Gram-Negative Bacteria [Returning user identified for 220,000 MDUs]*

MCB170086P Shikha Nangia, Syracuse University; Activation of Peptide Hormone Ghrelin via Human Ghrelin O-Acyltransferase [Returning user identified for 200,000 MDUs]*

MCB170090P Chun Wu, Rowan University; To Probe the Activation Mechanism of HER2 Directed Chimeric T-Cell Receptor (CAR) Using Molecular Dynamics Simulation with Explicit Membrane [Returning user identified for 460,000 MDUs]

MCB170093P Hans Peter Larsson, University of Miami; Selective Modulation of the IKs Channel with Poly-Unsaturated Fatty Acids (PUFAs) [Returning user identified for 460,000 MDUs]

MCB170100P Janice Robertson, Washington University; An Energetic Model of Tryptophan Destabilization of Membrane Protein Complexes [Returning user identified for 459,240 MDUs]

MCB170106P Yun Luo, Western University; Investigating HCN1 Channel Gating Mechanism Using Metal Bridges and Enhanced Sampling [Returning user identified for 460,000 MDUs]

MCB180080P Ira Kurtz, University of California, Los Angeles; Conformational Dynamics and Protein-Lipid Interactions in Different Transport States of SLC4 Proteins [Returning user identified for 416,000 MDUs]

MCB180088P Oliver Beckstein, Arizona State University; Conformational Transition of an “Electrical Motor” Protein [Returning user identified for 286,918 MDUs]*

MCB180091P William Goddard, California Institute of Technology; Structures and Mechanism for Signaling of the Two Distinct Conformations of the NTSR1– Gi1 Protein Complex Through MD Simulations [Returning user identified for 202,000 MDUs]

MCB190044P Jerome Lacroix, Western University of Health Sciences; Mechanism of Piezo1 Channel Inhibition by GsMTx4 [Returning user identified for 460,000 MDUs]

MCB190056P Wei Huang, Case Western Reserve University; Visualization of Enzymatic Steps at Atomic Resolution for Human 15-PGDH [Returning user identified for 213,865 MDUs]*

MCB190057P Jose Faraldo-Gomez, National Institutes of Health; Evaluation of Alternative Theories of Ion Channel Mechanosensation [Returning user identified for 460,000 MDUs]

MCB190076P Alexander Sodt, National Institutes of Health; Determining the Molecular Mechanism of Interferon-Induced Transmembrane Protein 3 (IFITM3) Antiviral Activity [Returning user identified for 460,000 MDUs]

MCB200062P Qiang Cui, Boston University; Molecular Dynamics Simulation of Allosteric Transition in Tetracycline Repressor [Returning user identified for 445,361 MDUs]

MCB200076P James McCarty, Western Washington University; Molecular Dynamics Study of Segmental Motion and Coupled Dynamics of an Intrinsically Disordered Region and a Folded Domain Within a Plant Villin Protein Fragment [Returning user identified for 300,000 MDUs]*

MCB200085P Jing Li, University of Mississippi; Structural Impacts of Arrhythmia-Associated Mutations on a Human Cardiac Nav Channel [Returning user identified for 460,000 MDUs]

MCB200093P Viviana Monje-Galvan, SUNY at Buffalo; Protein-Lipid Interactions in Mechanisms of Disease [Returning user identified for 230,000 MDUs]*

MCB210010P Thomas Szyperski, SUNY at Buffalo; Protein Core Water Penetration at the Onset of Cold Denaturation [Returning user identified for 230,000 MDUs]*

MCB210012P Gabriel Lander, The Scripps Research Institute; Investigating the Mechanism of Substrate Translocation in the Mitochondrial Protease LONP1 [Returning user identified for 460,000 MDUs]

MCB210015P Susan Marqusee, University of California, Berkeley; Determining Atomic-Level Mechanisms of Multidomain GPCR Activation [Returning user identified for 460,000 MDUs]

MCB210021P Sandhya Kortagere, Drexel University; Structural and Molecular Analysis of Wild Type and Mutant Plasmodium Falciparum ATPase4 [Returning user identified for 157,905 MDUs]

MCB220002P Joshua Vermaas, Michigan State University; Elucidating Phospholipid Identification and Loading Mechanisms in Phloem Lipid Associated Family Protein [New user identified for 346,232 MDUs]

MCB220003P Alexander Neimark, Rutgers University; Multiscale Modeling of Coronavirus Virions in the Respiratory System [New user identified for 230,000 MDUs]*

MCB220004P Danny Xu, Idaho State University; Exploring Molecular Mechanisms of Zebrafish Mechanosensitive Ion Channels with Molecular Dynamic Simulations [New user identified for 130,000 MDUs]*

MCB220005P Zeynep Gumus, Icahn School of Medicine at Mount Sinai; Molecular-Level Understanding of Receptor Binding of Engineered High-Density Lipoprotein Particles That Chaperone Bioactive Lipid Mediator Sphingosine 1-Phosphate (S1P) [New user identified for 306,606 MDUs]

MCB220008P Jin Yu, University of California, Irvine; Interrogating Transcription Factor and Enzyme Translocational Motions Along DNA/RNA Employing All-Atom Computational Microscope [New user identified for 260,000 MDUs]*

MCB220009P Marcel Baer, Pacific Northwest National Laboratory; Intrinsic Vs. Substrate Induced Loop Conformational Dynamics in KIN10 [New user identified for 230,000 MDUs]*

MCB220010P Gaetano Montelione, Rensselaer Polytechnic Institute; Mechanisms of Antimicrobial Drug Transport by Integral Membrane Protein MltA Interacting Protein (MipA) [New user identified for 454,950 MDUs]

MCB220011P Juan Vanegas, University of Vermont; Mechanical and Chemical Activation of the Angiotensin II Type 1 Receptor [New user identified for 447,166 MDUs]

MCB220012P Irina Kufareva, University of California, San Diego; The Tale of Two Receptors: Activation Dynamics of a Canonical GPCR and an Atypical 7TM Receptor in Response to a Shared Chemokine Ligand [New user identified for 460,000 MDUs]

MCB220013P Paul Spiegel, Western Washington University; Analysis of the Structural Dynamics of Coagulation Factor VIII [New user identified for 300,000 MDUs]

The time allocations for the 44 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 16,300,000 MDUs. Approximately 19.4% of MDUs were allocated to 10 proposals whose PIs have not received time on Anton or Anton 2 (identified as “new users”). These 10 new users represent approximately 23% of all investigators identified for a time allocation. Approximately 80.6% 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 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 21,435,000 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 2022 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,

Carol Post

Chair, Committee on Proposal Evaluation for Allocation of Supercomputing Time for the Study of Molecular Dynamics, Thirteenth Round