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October 19, 2012 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, Third Round. The committee evaluated submissions received in response to a Request for Proposals (RFP) for Biomolecular Simulation Time on Anton, a supercomputer specially designed and built by D.E. Shaw Research (DESRES) that allows for dramatically increased molecular dynamics simulations compared to other currently available resources. Over the past two years (October 1, 2010 September 30, 2012), DESRES has made available to the non-commercial research community node-hours on an Anton system housed at the Pittsburgh Supercomputing Center (PSC), based on the advice of previous National Research Council committees convened in the fall of 2010 and 2011. The success of the program has led DESRES to make the Anton machine housed at PSC available for an additional 3,700,000 node-hours over the 9 months following October 2012, 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 aforementioned RFP. The committee of 15 was chaired by Dr. L. Mario Amzel, Professor and Director, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, School of Medicine. The committee members were selected for their expertise in molecular dynamics simulations, as well as their experience in the subject areas represented in the 52 proposals that were considered by the committee. They comprised a cross section of the biomolecular dynamics field in academia, industry and government including an array of both senior and junior investigators. The goal of the third RFP for Biomolecular Simulation Time on Anton has been 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 special capabilities allow multi-microsecond to millisecond simulation timescales, which previously had been 2

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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 Anton RFP described the three criteria against which the committee was asked to evaluate proposals: x 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 proposed studies. x 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. x 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 brief progress reports. Following guidance provided by DESRES and PSC, the committee drew on these progress reports 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 to determine whether they were technically feasible for simulation on Anton. A member of the PSC staff was also present as an observer throughout the review committee's discussions to address technical specification questions that arose. The committee was asked to identify proposals that best met the selection criteria. As in the previous two rounds of time allocations for Anton, 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 try to allocate approximately 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 also 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 15 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 no proposal was evaluated by a reviewer from the applicant's same institution or who had a collaborative relationship with an applicant. The NRC committee held its meeting in Washington, D.C. on September 7, 2012. 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. The committee then considered the slate of proposals as a whole, came to a 3

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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. The committee concluded that the 45 proposals listed below best met the selection criteria set forth in the RFP for Biomolecular Simulation Time on Anton. Of these 45 proposals, 12 proposals were selected for a modified allocation (identified below with an *). Detailed comments for each of the 52 proposals considered by the committee are included in Appendix B. In numerical order by proposal submission number, the proposals that the committee concluded best met the selection criteria are: PSCA12004P Structural and Dynamic Effects of Antifreeze Proteins on Water; PI: Lin, Tufts University [New user, identified for 65,000 node-hours]* PSCA12005P Dynamic coupling and fluctuations in protein-protein complexes; PI: Buck, Case Western Reserve University [Returning user, identified for 50,000 node-hours] PSCA12006P Atomistic mechanism of the nucleotide-dependent kinesin conformational changes assisted by the microtubule; PI: Hwang, Texas A&M University [Returning user, identified for 100,000 node-hours] PSCA12008P Watching a small chemical chaperone in action: a dynamical approach using the Anton supercomputer; PI: Berne, Columbia University [Returning user, identified for 100,000 node-hours] PSCA12010P Dynamics of the Early Translational Machinery; PI: Luthey-Schulten, University of Illinois [Returning user, identified for 100,000 node-hours] PSCA12012P Microsecond scale simulations to characterize mutations and phosphorylations in full length troponin; PI: McCammon, University of California San Diego [Returning user, identified for 100,000 node-hours] PSCA12013P Hidden Intermediates and Salt-induced Refolding; PI: Huo, Clark University [Returning user, identified for 100,000 node-hours] PSCA12014P Predicting experimental signatures of lateral phase separation in ternary bilayers: Anchored domains or floating rafts?; PI: Lyman, University of Delaware [Returning user, identified for 100,000 node-hours] PSCA12016P Elucidating the mechanism of pH-gating, solute selectivity, and flux of UreI, the urea channel of Helicobacter pylori; PI: Luecke, University of California Irvine [Returning user, identified for 80,000 node-hours] PSCA12017P 20 microsecond simulation of charge-shift electron transfer reaction in bacterial photosynthesis; PI: Matyushov, Arizona State University [New user, identified for 45,000 node-hours] PSCA12018P Exploring the Membrane Selectivity of Antimicrobial Peptides; PI: Kim, University of California San Diego [Returning user, identified for 59,000 node-hours] PSCA12021P Molecular Dynamics Simulations of p53-DNA Complexes; PI: Rohs, University of Southern California [New user, identified for 65,000 node-hours]* 4

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PSCA12023P MD and NMR characterizations of psychrotrophic, mesophilic, and thermophilic enzymes; PI: Palmer, Columbia University [New user, identified for 100,000 node- hours] PSCA12024P Dynamics and Ligand Binding by HSP40 and HSP104 Chaperones in Relation to Iron-Sulfur Cluster Biogenesis and Protein Disaggregation; PI: Scheraga, Cornell University[Returning user, identified for 65,000 node-hours]* PSCA12025P Starting transcription by bacterial RNA polymerase; PI: Thirumalai, University of Maryland [Returning user, identified for 100,000 node-hours] PSCA12026P Altering the allosteric communication between an active-state receptor and its cognate G protein: Unconstrained molecular dynamics simulation studies of the metarhodopsin II-Gt(GDP) mutant complexes; PI: Beratan, Duke University [Returning user, identified for 50,000 node-hours] PSCA12027P Understanding the Dynamics of Human Histone Deacetylase 8: From Regulation to Substrate Binding; PI: Coveney, Yale University [Returning user, identified for 100,000 node-hours] PSCA12028P Determining the mechanisms of protein folding in membranes; PI: Gumbart, Argonne National Laboratory [New user, identified for 100,000 node-hours] PSCA12029P Mechanisms of transition from open to occluded state in the outward-facing structure of sodium-coupled leucine transporter; PI: Bahar, University of Pittsburgh [Returning user, identified for 100,000 node-hours] PSCA12030P Anton Simulations to Show the Role of Environment and Co-factors in Conformational Change of the SERCA (Ca-ATPase) Pump; PI: Woolf, Johns Hopkins University [Returning user, identified for 100,000 node-hours] PSCA12031P Understanding Kinase Regulation through Microsecond Timescale Simulations of Protein Kinase A; PI: Amaro, University of California San Diego [New user, identified for 100,000 node-hours] PSCA12032P Mechanism of agonist/antagonist sensor in opioid receptors - role of water molecules; PI: Palczewski, Case Western Reserve University [New user, identified for 65,000 node-hours]* PSCA12033P The determinants of C-type inactivation and recovery in the KcsA channel; PI: Roux, University of Chicago [Returning user, identified for 100,000 node-hours] PSCA12034P Activation of the G-protein coupled receptor squid rhodopsin on the microsecond timescale; PI: Tobias, University of California Irvine [Returning user, identified for 100,000 node-hours] PSCA12035P Conformational changes in lactose permease of E. coli to understand spin label dynamics and helix movements; PI: Klauda, University of Maryland [Returning user, identified for 50,000 node-hours] PSCA12036P Long Time Scale Molecular Dynamics Simulation of Protein Folding; PI: Gruebele, University of Illinois [Returning user, identified for 100,000 node-hours] 5

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PSCA12038P Converging simulations of a DNA duplex and explorations of a DNA mini- circle on the microsecond timescale using MD on Anton; PI: Cheatham, University of Utah [Returning user, identified for 100,000 node-hours] PSCA12040P Multi-microsecond simulations of two-domain proteins; PI: Chong, University of Pittsburgh [Returning user, identified for 50,000 node-hours] PSCA12041P Atomistic modeling of ion conduction through voltage-sensing domains; PI: Freites, University of California Irvine [Returning user, identified for 100,000 node-hours] PSCA12043P Nascent protein folding inside the ribosomal exit tunnel; PI: Schulten, University of Illinois [Returning user, identified for 100,000 node-hours]* PSCA12044P Sequencing DNA Using MspA; PI: Aksimentiev, University of Illinois [Returning user, identified for 100,000 node-hours] PSCA12045P Exploration of the Human Adenovirus Protease Activation Pathway via Long Timescale Molecular Dynamics Simulations; PI: Walker, University of California San Diego [Returning user, identified for 65,000 node-hours]* PSCA12047P Characterizing Ion-coupled Structural Transitions in Secondary Membrane Transporters; PI: Tajkhorshid, University of Illinois [Returning user, identified for 100,000 node-hours]* PSCA12048P Examining the Role of Lipid-Protein Interactions in the Activation of Membrane Proteins Using Microsecond-scale Molecular Dynamics Simulation; PI: Allen, University of California Davis [Returning user, identified for 100,000 node-hours] PSCA12049P Molecular Dynamics Simulations of PTEN in Solution and on the Lipid Membrane; PI: Nanda, Carnegie Mellon University [New user, identified for 65,000 node- hours]* PSCA12050P Using microsecond scale dynamics to assist the development of inhibitors of Ca2+-independent phospholipase A2 enzymes; PI: Dennis, University of California San Diego [New user, identified for 100,000 node-hours] PSCA12051P How do slow motions regulate a kinase's activity at the atomistic level?; PI: S. Taylor, University of California San Diego [Returning user, identified for 50,000 node-hours] PSCA12052P The substrate-binding induced conformational transitions in HepI: Structure, mechanism, and conformational dynamics of a GT-B enzyme; PI: E. Taylor, Wesleyan University [New user, identified for 50,000 node-hours] PSCA12053P Detailed characterization of the gp120/CD4/Ibalizumab complex; PI: Langmead, Carnegie Mellon University [Returning user, identified for 50,000 node-hours] PSCA12054P Recognition Mechanisms of Membrane-targeting Protein Domains; PI: Voth, University of Chicago [New user, identified for 86,000 node-hours] PSCA12055P Entropy in Protein-Ligand Binding via Simulations at the Microsecond Time Scale: Exploring the Consequence of Protease Mutations; PI: Gilson, University of California San Diego [Returning user, identified for 100,000 node-hours] 6

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PSCA12056P Simulating Gating Transitions in Glutamate Receptors; PI: Kurnikova, Carnegie Mellon University [New user, identified for 65,000 node-hours]* PSCA12057P Microsecond MD Studies of Allosteric Drugs in the Imidazole Glycerol Phosphate Synthase; PI: Batista, Yale University [Returning user, identified for 65,000 node- hours]* PSCA12058P Polycyclic Natural Products and Analogues through Computational Enzyme Engineering; PI: Pande, Stanford University [Returning user, identified for 65,000 node-hours]* PSCA12059P Structural basis for the Thermostability of mutant G-protein coupled receptors; PI: Vaidehi, City of Hope Medical Center [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 3,655,000 node-hours. Of these proposals, 26 were identified at the approximately 100,000 node-hour level and 19 at the approximately 50,000 node-hour level.1 A total of 956,000 node-hours were allocated to 13 proposals whose principal investigator did not receive time on Anton during the past two years (identified as "new users"). The remaining 2,699,000 node-hours are allocated to 32 proposals from investigators who had received previous round time allocations (indentified 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 encourages D.E. Shaw Research and the Pittsburgh Supercomputing Center to establish a collective repository to share data generated, because the trajectories obtained may be of use to other investigators in the community. The committee would like to thank D.E. Shaw Research, the Pittsburgh Supercomputing Center, and all of the 2012 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, L. Mario Amzel Chair cc: Dr. Markus Dittrich, Pittsburgh Supercomputing Center Dr. Warren Muir, National Research Council Dr. Frances Sharples, National Research Council 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. 7

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Appendices: A. Table 1: Proposals Reviewed by the Committee B. Individual Proposal Summary Evaluations C. Proposal Review 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 8