Report of the Committee on Proposal
Evaluation for Allocation of Supercomputing
Time for the Study of Molecular Dynamics,
Eighth Round

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

Board on Life Sciences

Board on Chemical Sciences and Technology

Division on Earth and Life Studies

A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

October 23, 2017

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, Eighth 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 7 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 National Research Council committees. As in prior rounds, the goal of the eighth 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 simulations. 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 2017, 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 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 18 was chaired by Dr. William Goddard, Ferkel Professor of Chemistry, Materials Science, and Applied Physics at the California Institute of Technology. The committee members were selected for their expertise in molecular dynamics simulations and experience in the subject areas represented in the 79 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. During the application process, applicants had the opportunity to suggest experts they felt would be suitable committee members as well as provide names of experts they would not like to review their proposal.

The Anton 2 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 time on Anton 2 rather than conventional supercomputers 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 and demonstrated progress from previous Anton allocations.

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 whether they were technically feasible for simulation on Anton 2. Proposals that passed this screening were submitted to the committee for review. 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. Anton 2 time allocations of 460,000 MDUs 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 18 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. Care was taken to ensure that no proposal was assigned a reviewer that the applicant had identified as being an inappropriate reviewer.

The committee held its meeting in Washington, DC, on August 11, 2017. 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 2. Detailed comments for each of the 79 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 60 proposals, 38 proposals were selected for a modified allocation (identified below with an *).

In numerical order by proposal submission number, the proposals judged by the committee as best meeting the selection criteria of the RFP are:

PSCA17004P Yinghao Wu, Albert Einstein College of Medicine; Computational Study of Binding Between Membrane Receptors and Multivalent Ligands in T-Cell Activation [New user identified for 100,000 MDUs]*

PSCA17006P Jerome Lacroix, Western University of Health Sciences; Chemical Activation of the Mechanosensitive Piezo1 Channel with Yoda1 [New user identified for 230,000 MDUs]*

PSCA17007P Harol Weinstein, Weill Cornell Medical College, Cornell University; Molecular mechanisms of lipid scrambling by TMEM16 proteins [Returning user identified for 297,000 MDUs]*

PSCA17008P Wonpil Im, Lehigh University; Effects of N-Glycan Composition on Binding of Igg1 to CD16A [Returning user identified for 307,000 MDUs]*

PSCA17009P Jeffery Klauda, University of Maryland; Antagonist and Glycosylation Effects on the Biological Function of the Serotonin Receptor [Returning user identified for 395,025 MDUs]*

PSCA17010P Michael Levine, Weill Cornell Medicine, Cornell University; Investigation of the Allosteric Modulation Intracellular Gating by the Primary Substrate Site and the Secondary Allosteric Site in the Human Serotonin Transporter hSERT [New user identified for 220,000 MDUs]*

PSCA17012P Sharon Loverde, CUNY College of Staten Island; Molecular Dynamics Simulations of the Interaction of Drug Amphiphiles with a Model Phospholipid Membrane [Returning user identified for 196,085 MDUs]

PSCA17014P Marta Filizola, Icahn School of Medicine at Mount Sinai; Mechanistic Insights into the Binding and Action of Allosteric Modulators of Opioid Receptors [Returning user identified for 460,000 MDUs]

PSCA17015P Wonmuk Hwang, Texas A&M University; Atomistic Mechanism for the Stepping Motion of a Kinesin Dimer [Returning user identified for 460,000 MDUs]

PSCA17016P Yuri Lyubchenko, University of Nebraska Medical Center; MD Simulations of Interactions and Misfolding of Amyloid Beta (Aβ) Proteins [Returning user identified for 230,000 MDUs]*

PSCA17017P Chun Wu, Rowan University; Probe Activation Mechanism of Membrane GPCR Receptors Using All-Atom Molecular Dynamics Simulation with Explicit Membrane [New user identified for 100,000 MDUs]*

PSCA17019P Themis Lazaridis, City College of New York; Structures and Pathways of Peptide-Stabilized Membrane Pores [Returning user identified for 140,000 MDUs]*

PSCA17021P Hans Larsson, University of Miami; Identifying Specific Interactions Between Ion Channels, Lipids, and Lipid-Like Drug Candidates in Complex Cardiac Membranes [New user identified for 410,000 MDUs]

PSCA17023P Benoit Roux, University of Chicago; Elucidating the Allosteric Coupling Mechanism Between the Cytoplasmic and the Transmembrane Domains of the Calcium SERCA Pump ATPase [Returning user identified for 460,000 MDUs]

PSCA17025P Baron Chanda, University of Wisconsin; Non-Canonical Voltage-Sensor Pore Coupling in the Hyperpolarized Cyclic Nucleotide Gated Channel [New user identified for 150,000 MDUs]*

PSCA17027P Richard Pastor, National Institutes of Health; Structure of Apolipoprotein A-I in Nascent and Mature High-Density Lipoproteins [Returning user identified for 230,000 MDUs]*

PSCA17028P Peter Searson, Johns Hopkins University; Quantifying the Binding Affinity of the P-Glycoprotein Multidrug Efflux Pump Using Unbiased Long-Timescale Molecular Dynamics Simulations [New user identified for 230,000 MDUs]*

PSCA17029P Wenjun Zheng, University at Buffalo, SUNY; Molecular Dynamics Simulation of the Heat Activated Gating of TRPV1 Channel [New user identified for 230,000 MDUs]*

PSCA17031P Devarajan Thirumalai, The University of Texas at Austin; The Recognition of DNA Promoter in Bacterial RNA Polymerase [Returning user identified for 100,000 MDUs]*

PSCA17032P Michael Feig, Michigan State University; Microsecond Diffusion of Proteins and RNA Near Chromosomal DNA [Returning user identified for 460,000 MDUs]

PSCA17034P Zaida Luthey-Schulten, University of Illinois at Urbana-Champaign; Transmembrane Signaling Mechanisms in a Bacterial Chemoreceptor [Returning user identified for 460,000 MDUs]*

PSCA17035P Jeff Wereszczynski, Illinois Institute of Technology; Understanding the Role of LPS Modification on Antimicrobial Peptide Interactions [Returning user identified for 230,000 MDUs]*

PSCA17036P David Cowburn, Albert Einstein College of Medicine; FG Repeat Domain Interactions of the Nuclear Pore by Simulation and Experiment [Returning user identified for 460,000 MDUs]

PSCA17038P Jean-Pierre Leburton, University of Illinois at Urbana-Champaign; Computational Study of Genetic and Epigenetic Sensing Using Multi-Layered 2D Solid-State Nanopores [New user identified for 242,640 MDUs]

PSCA17041P Andrew Harris, Rutgers New Jersey Medical School; Permeation of Biological Molecules Through a Connexin Channel [New user identified for 100,000 MDUs]*

PSCA17042P Martin Gruebele, University of Illinois Urbana-Champaign; Protein Folding in a Simulated Cytoplasm [Returning user identified for 460,000 MDUs]

PSCA17043P Rommie Amaro, University of California, San Diego; Investigating Chemokine Receptor Dynamics and Druggability by Ensemble Based Approaches [Returning user identified for 260,000 MDUs]*

PSCA17044P Huan-Xiang Zhou, Florida State University; Study of Maltose-MBP Binding Kinetics Based on Markov State Modeling [New user identified for 230,000 MDUs]*

PSCA17045P Vladimir Yarov-Yarovoy, University of California Davis; State-Dependent Drug Modulation of Sodium Channels [Returning user identified for 230,000 MDUs]*

PSCA17046P Gregory Voth, The University of Chicago; Functional Importance of Membrane Nanodomains in HIV Replication [Returning user identified for 150,968 MDUs]*

PSCA17048P Eduardo Perozo, The University of Chicago; Mechanism of Conformational Transitions in the Voltage-Sensing Domain of Ci-VSP [Returning user identified for 460,000 MDUs]

PSCA17049P Alemayehu Gorfe, The University of Texas Health Science Center at Houston; Membrane Orientation Dynamics of Lipidated Small GTPases and Self-Assembly of K-Ras [Returning user identified for 267,912 MDUs]*

PSCA17050P Ron Dror, Stanford University; Determining How GPCRs Selectively Stimulate Intracellular Signaling Proteins [Returning user identified for 284,000 MDUs]*

PSCA17051P David P. Hoogerheide, National Institute of Standards and Technology; Molecular Mechanisms of the Voltage-Dependent Anion Channel Regulation by Tubulin Isotypes [Returning user identified for 360,000 MDUs]

PSCA17052P Wenwei Zheng, Arizona State University; Investigating the Molecular Interactions Controlling the Liquid Droplet Formation by Intrinsically Disordered Proteins [New user identified for 50,549 MDUs]*

PSCA17053P Douglas Tobias, University of California, Irvine; Atomistic Modeling of Water Permeation in Aquaporin 0-Calmodulin Complexes [Returning user identified for 235,000 MDUs]

PSCA17054P Edward Lyman, University of Delaware; Rationalizing Cholesterol-Dependent Function of the A2A Adenosine Receptor [Returning user identified for 441,301 MDUs]

PSCA17056P J. Alredo Freites, University of California, Irvine; Molecular Modeling Studies of Eye Lens Proteins at Physiological Concentrations [Returning user identified for 230,000 MDUs]*

PSCA17057P Kendall N. Houk, University of California, Los Angeles; Understanding the Molecular Basis of Hapalindole and Fischerindole Biogenesis Catalyzed by Stig Cyclases [Returning user identified for 210,000 MDUs]

PSCA17058P Dimitrios Morikis, University of California, Riverside; Large-Scale, Functional Conformational Transitions in Complement C3 [Returning user identified for 460,000 MDUs]

PSCA17059P Alexander Sobolevsky, Columbia University; Modeling of the Mechanisms of Ion Selectivity and the Protein Structure Dynamics of the Transient Receptor Potential Channels [New user identified for 100,000 MDUs]*

PSCA17061P Michael Grabe, University of California, San Francisco; Unraveling the Mechanism of Activation in K2P Channels [Returning user identified for 460,000 MDUs]

PSCA17062P Lucy Forrest, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Exploring the Conformational Space of Osmotic Stress-Sensing Domains in a Membrane Transport Protein [New user identified for 460,000 MDUs]

PSCA17063P Eric May, University of Connecticut; Membrane Disruption by Non-Enveloped Viral Peptides: Understanding Aspects of Peptide Aggregation and Peptide-RNA Interactions [Returning user identified for 131,500 MDUs]*

PSCA17064P Nikolai Smolin, Loyola University Chicago; Regulatory Interactions Between SERCA and PLB Investigated by Molecular Dynamics Simulations [New user identified for 150,000 MDUs]*

PSCA17067P Matthias Buck, Case Western Reserve University; Simulations of Plexin and Eph Transmembrane Receptors [Returning user identified for 100,000 MDUs]*

PSCA17069P Peter Freddolino, University of Michigan Medical School; Accurate Modeling of Transcription Factor-DNA Interactions Enabled by Extreme Molecular Dynamics Simulations [New user identified for 246,588 MDUs]

PSCA17072P Thomas Miller, California Institute of Technology; Understanding the Mechanism and Biological Origins of Force Induced Restarting of Protein Synthesis in SecM-Stalled Ribosomes [Returning user identified for 450,000 MDUs]

PSCA17073P Shikha Nangia, Syracuse University; Role of S-Palmitoylation on the Blood-Brain Barrier Tight Junction Interface [New user identified for 100,000 MDUs]*

PSCA17074P Diwakar Shukla, University of Illinois at Urbana-Champaign; Mechanism of Sugar Transport in Rice via SWEET Family Transporters [Returning user identified for 150,000 MDUs]*

PSCA17075P Mahmoud Moradi, University of Arkansas; Lipid-Dependent Alternating Access Mechanism in ABC Exporters [Returning user identified for 100,000 MDUs]*

PSCA17076P Janice Robertson, The University of Iowa; Identifying the Physical Driving Forces for CLC Dimerization in Lipid Bilayers [New user identified for 120,000 MDUs]*

PSCA17077P Graham Fleming, University of California, Berkeley; Microsecond Molecular Dynamics Simulations of the Transmembrane Proton Gradient Sensor Protein PsbS Required for Rapid Induction of Non-Photochemical Quenching of Chlorophyll in Light Harvesting Plants [New user identified for 100,000 MDUs]*

PSCA17078P Susan Taylor, University of California San Diego; Investigating the Kinase Molecular Assemblies to Understand Allostery and Target Kinase Protein-Protein Interactions as Cancer Therapy [Returning user identified for 368,000 MDUs]*

PSCA17079P David Agard, University of California, San Francisco; Conformational Dynamics of the Molecular Chaperone Heat Shock Protein 90 (HSP90) [Returning user identified for 230,000 MDUs]*

PSCA17080P Bernard Brooks, National Institutes of Health; The HCN1 Channel: Structural and Functional Modulation Due to Ligand Binding [New user identified for 230,000 MDUs]*

PSCA17081P Sandrasegaram Gnanakaran, Los Alamos National Laboratory; Investigating the Dynamics of Membrane-Anchored RAS/RAF-RBD/RAF-CRD Ternary Complexes [New user identified for 100,000 MDUs]*

PSCA17084P HarishVashisth, University of New Hampshire; Toward a Full-Length Structure of the Insulin Receptor in Apo and Hormone-Bound Forms [Returning user identified for 230,000 MDUs]*

PSCA17085P Igor Vorobyov, University of California, Davis; Molecular Determinants of State Dependent hERG Channel- Drug and Hormone Interactions [Returning user identified for 460,000 MDUs]

PSCA17087P Aleksei Aksimentiev, University of Illinois at Urbana-Champaign; Molecular Mechanism of Nucleosomal Stability Controlled by the DNA Sequence [Returning user identified for 300,000 MDUs]*

The time allocations for the 60 proposals identified by the committee as best meeting the selection criteria for time allocations total approximately 15,813,569 MDUs. Approximately 25% MDUs were allocated to proposals whose principal investigator have not received time on Anton during the past 5 years (identified as “new users”). Approximately 75% of the MDUs are allocated to proposals from investigators who have 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 more than 31 million MDUs. 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 2017 Anton 2 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 2 and are looking forward to seeing the important new results from the Anton users.

Sincerely,

William A. Goddard III

Chair

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. Board on Life Sciences, Board on Chemical Sciences and Technology, and the National Academies

F. Acknowledgment of Report Reviewer

G. Disclosure of Conflicts of Interest

* These appendices are not available to the public.

APPENDIX C

PROPOSAL EVALUATION CRITERIA

The committee used the points below to help guide its review of the proposals. The reviewers were asked to comment on the strengths and weaknesses of the proposals by considering the following:

Level of scientific merit. This should be evaluated by considering:

1. Potential to advance understanding of an important problem or question in the field; potential for breakthrough science resulting in new discoveries and understanding
2. Impact that successful completion of the proposed research would have on the knowledge, methods, and current barriers in the field
3. Project is scientifically and technologically feasible with clear, well-developed, and appropriate goals, objectives, and approach to the proposed studies

Justification for requested time allocation. This should be evaluated by considering:

1. Clear and well-justified need for time on Anton rather than conventional supercomputers
2. 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. This should be evaluated by considering:

1. Appropriate experience and training to successfully conduct the proposed studies
2. Evidence of knowledge and prior experience with molecular simulations
3. Past publications and demonstrated progress from previous Anton allocations

APPENDIX D

ROSTER AND BIOGRAPHICAL SKETCHES OF COMMITTEE MEMBERS

COMMITTEE ON PROPOSAL EVALUATIONS FOR ALLOCATION OF SUPERCOMPUTING TIME FOR THE STUDY OF MOLECULAR DYNAMICS, EIGHTH ROUND

Chair

WILLIAM A. GODDARD III, California Institute of Technology

Members

NILESH BANAVALI, Wadsworth Center of the New York State Department of Health

JAMES BRIGGS, University of Houston

MARIA BYKHOVSKAIA, Wayne State University

VINCENZO CARNEVALE, Temple Materials Institute

JIANHAN CHEN, University of Massachusetts

MANOLIS DOXASTAKIS, University of Tennessee

GIACOMO FIORIN, Temple Materials Institute

JAMES C. GUMBART, Georgia Institute of Technology

MARGARET JOHNSON, Johns Hopkins University

IVAYLO IVANOV, Georgia State University

ANDRZEJ KLOCZKOWSKI, Research Institute at Nationwide Children’s Hospital

JIANING LI, University of Vermont

DIANE LYNCH, University of North Carolina

CHRISTOPHER ROWLEY, Memorial University

MARKUS SEELIGER, Stony Brook University Medical School

LEI SHI, National Institutes of Health

CHUNG WONG, University of Missouri-St. Louis

Project Staff

ANDREA HODGSON, Project Director, Board on Life Sciences

ELIZABETH BOYLE, Program Officer, Board on Chemical Sciences and Technology

ANGELA KOLESNIKOVA, Senior Program Assistant, Board on Life Sciences

KEEGAN SAWYER, Senior Program Officer

KATIE BOWMAN, Senior Program Officer

BIOGRAPHICAL SKETCHES OF COMMITTEE MEMBERS

CHAIR

William A. Goddard III, PhD, NAS, is the Charles and Mary Ferkel Professor of Chemistry and Applied Physics, and Director, Materials and Process Simulation Center at the California Institute of Technology. He obtained his B.S. from the University of California, Los Angeles, in 1960 and his Ph.D. from the California Institute of Technology, 1965. The long-term objective of Professor Goddard’s research has been to describe the properties of chemical, biological, and materials systems directly from first principles (without the necessity of empirical data). To accomplish this the group has been developing new theory, new methods, and new software. The group’s approach builds from Quantum Mechanics (QM) through a hierarchy of more approximate methods suitable for longer length and times scales as indicated in the figure including Molecular Dynamics (MD), mesoscale dynamics, and macroscopic dynamics. His focus in biochemical systems is on structure, ligand binding, and activation of GPCR membrane bound proteins.

MEMBERS

Nilesh Banavali, PhD, is a Research Scientist at the Wadsworth Center of the New York State Department of Health and an Assistant Professor in the School of Public Health at the University at Albany, SUNY. The primary goal of his research is to use computational calculations and refined analysis techniques to optimally extract free energy landscapes describing biologically relevant macromolecular conformational change. Dr. Banavali also develops techniques to facilitate validation of computational predictions with structural and biochemical data. He received his PhD from the University of Maryland in 2001 for studies on nucleic acid force fields and base flipping with Alexander MacKerell, Jr. He pursued postdoctoral training at Weill Medical College of Cornell University and the University of Chicago with Benoît Roux on implicit and implicit/explicit solvent models and free energy characterization of conformational change and allostery in macromolecules.

James Briggs, PhD, is a Professor within the Biology and Biochemistry Department at the University of Houston and is also Associate Dean for Faculty Affairs. Dr. Briggs received his PhD in Chemistry from Purdue University. His research focuses on computational studies of protein structure and function, inhibitor design, investigations of possible inhibitor resistance pathways, and development of methods for the above project areas. Targets for these studies include those important in the treatment of AIDS, cancer, bacterial infections, and other disease states.

Maria Bykhovskaia, PhD, is a Professor at the Department of Neurology at Wayne State University (WSU). Dr. Bykhovskaia obtained her PhD in Biophysics from the Russian Academy of Science, and postdoctoral training in Neuroscience from the University of Virginia. She held a faculty appointment at Lehigh University in Pennsylvania, and then was a Chair of the Neuroscience Department in the Universidad Central del Caribe in Puerto Rico. She joined the WSU faculty in 2015. Her lab combines electrophysiology, live confocal imaging, electron microscopy, and computational modeling to investigate how presynaptic molecular machinery affects synaptic transmission and plasticity. Dr. Bykhovskaia maintains an active research program funded by the National Institutes of Health and the National Science Foundation. She has numerous publications in the area of presynaptic mechanisms and modeling of the transmitter release machinery.

Vincenzo Carnevale, PhD, is a Research Associate Professor at Temple University with a research focus on Statistical Physics & Computational Biology. He received his PhD in the field of Functional and Structural Genomics in the Statistical and Biological Physics Sector at the International School for Advanced Studies, Trieste, Italy. He received his bachelor’s and master’s degrees in Physics at the

University of Pisa, Italy. He developed interest in quantitate biology from a background in condensed matter physics with the goal of identifying the protein sequence features responsible for distinct biological function in different protein families.

Jianhan Chen, PhD, is a Professor in the Department of Chemistry and Department Biochemistry and Molecular Biology at University of Massachusetts Amherst. The general focus of his research is on theoretical and computational studies of biomolecular structure, dynamics, and function. He and his team are particularly interested in modeling weakly stable peptides and proteins and understanding their roles in important biological processes, including regulation of transcription and translation, signal transduction, and disease-related protein misfolding. Furthermore, Dr. Chen’s research team applies computer modeling to determine the selectivity, transport, and gating mechanisms of designed anion selective channels. Dr. Chen has a PhD in Chemical and Material Physics from the University of California, Irvine.

Manolis Doxastakis, PhD, graduated from the National Technical University of Athens with a Diploma in Chemical Engineering in 1996. His diploma thesis focused on the synthesis and characterization of polylactic acid for biomedical applications. He then moved to the University of Patras (Greece) and received his MS and PhD in Materials Science and Chemical Engineering, respectively, in 2002. During his graduate studies, Dr. Doxastakis performed research in polymeric materials using a combined computational and experimental approach. He applied these methods in the Institute of Chemical Engineering and High Temperature Chemical Processes, Patras (Greece); the Institute of Electronic Structure and Laser, Heraklion (Greece); the Commonwealth Scientific and Industrial Research Organisation, Melbourne (Australia); and the Institut Laue-Langevin, Grenoble (France). In 2003, he moved to the University of Wisconsin–Madison as a postdoctoral researcher in the Chemical and Biological Engineering department where he remained for 3 years. In 2007, Dr. Doxastakis joined the University of Houston as an Assistant Professor of Chemical and Biomolecular Engineering forming a computational research group that studied interfacial phenomena in materials science and biophysics with custom highly efficient parallel algorithms. In 2014, he moved to Argonne National Laboratory and the Institute for Molecular Engineering working on a new framework for the characterization of nanomaterials in patterning applications, combining advanced X-ray scattering methods with molecular simulations. In Fall 2016, Dr. Doxastakis joined the University of Tennessee in Knoxville as an Associate Professor of Chemical and Biomolecular Engineering. Dr. Doxastakis’s research spans a broad spectrum of soft matter that covers polymer melts, blends, copolymers, as well as lipid membranes and protein assemblies. His articles are highlighted in the front cover of high impact journals and are consistently cited. Dr. Doxastakis has delivered more than 20 invited lectures, chaired multiple sessions on multiscale modeling in national conferences and serves as the reviewer for more than 20 scientific journals.

Giacomo Fiorin, PhD, is an Associate Professor of Research at the Institute for Computational Molecular Science at Temple University. He is a computational scientist with experience in the fields of molecular biophysics, soft matter systems, molecular dynamics, free-energy calculations, and high-performance computing. Dr. Fiorin received an MS in Physics from the University of Padua, with a dissertation on the theory of proton emission from deformed nuclei, and a PhD in Statistical and Biological Physics from the International School for Advanced Studies in Trieste on the activation of calcium-signaling proteins by calmodulin. During his postdoctoral training at the University of Pennsylvania and Temple University, he used MD simulations to characterize the molecular mechanisms of influenza infection and drug resistance, and to predict the structure and permeability of the lipid matrix of mammalian skin. In the period 2011–2015, Dr. Fiorin was also the biostatistics instructor in the College of Science and Technology at Temple, training hundreds of undergraduate and graduate students of biology, pharmacy, health professions, and engineering. Since 2008, Dr. Fiorin is the lead developer of the Collective Variables module (Colvars), a software for free energy calculations and enhanced sampling distributed with the simulation and analysis programs NAMD, VMD, and LAMMPS. Since 2010, Dr.

Fiorin authored numerous proposals that were awarded through the XSEDE, INCITE and PRAC supercomputing allocation programs, and is a reviewer for scientific journals and funding/supercomputing agencies.

James C. (JC) Gumbart, PhD, is an assistant professor of physics at the Georgia Institute of Technology in Atlanta, Georgia. He obtained his BS from Western Illinois University in 2003 and his PhD in Physics from the University of Illinois at Urbana-Champaign in 2009 under the mentorship of Klaus Schulten, focusing on the area of computational biophysics. After 2 years as a postdoctoral fellow at Argonne National Lab working with Benoit Roux, he started his lab at Georgia Tech in early 2013. His lab carries out molecular dynamics simulations aimed primarily at understanding the composition, construction, and function of the Gram-negative bacterial cell envelope.

Margaret Johnson, PhD, joined the Biophysics faculty at Johns Hopkins University in 2013. She received her BS in Applied Math from Columbia University and her PhD in BioEngineering from University of California, Berkeley. She completed postdoctoral training in the Laboratory of Chemical Physics at the National Institutes of Health in Bethesda, Maryland. Her research focuses on understanding how the individual interactions between thousands of diverse components in the cell generate order and collective function at the right time and the right place. She develops theoretical and computational approaches to study the evolution and mechanics of dynamic systems of interacting and assembling proteins.

Ivaylo Ivanov, PhD, received his PhD in Chemistry from the University of Pennsylvania in Philadelphia. In 2009 he moved to Georgia State University in Atlanta where he established an independent multidisciplinary research program at the interface of the computational and biological sciences. Specifically, his research address topical issues in the area of DNA replication and DNA repair. DNA replication is a major target for cancer therapies, while efficient repair antagonizes those same therapies. Understanding the inner workings of the replisome–the complex molecular machine that accomplishes replication of chromosomal DNA–is undeniably among the great challenges in the biomedical sciences. Presently, the structures of many individual components of the replisome have been solved. How these components come together to form a functioning molecular machine is still unknown. Recent work in Dr. Ivanov’s group has focused on the function and interactions of important core replisomal proteins, e.g., DNA polymerases, Flap Endonuclease 1 (FEN1), DNA ligase (Lig1), and DNA clamps (PCNA and a related checkpoint protein, Rad9-Hus1-Rad1 (9-1-1)). Understanding the coordinated assembly and function of these proteins in replication is an important problem. However, no high-resolution structures exist for the functional complexes, and limited information is available on the structural basis for coordination of DNA replication and repair activities. Such gaps in understanding are largely due to the dynamic nature of these assemblies, which challenge conventional structural approaches. To overcome this problem, Dr. Ivanov’s group has employed hybrid methods, combining computational modeling with experimental validation by electron microscopy (EM) and small angle X-ray scattering (SAXS). All three areas, computational modeling, EM, and SAXS are rapidly advancing. Computational methods bridge the gap from low-resolution SAXS and EM techniques to high-resolution models and allow determination of coordination controlling elements in biological assemblies. Work has appeared in prominent journals, e.g., the Journal of the American Chemical Society, Proceedings of the National Academy of Sciences, Angewandte Chemie International Edition, and Nucleic Acids Research. Findings have been highlighted in press releases and have been featured by Faculty of 1000 and by the Oak Ridge Leadership Computing Facility (OLCF) at the Oak Ridge National Lab. Dr. Ivanov’s group is also taking advantage of the petascale supercomputing facilities available through National Science Foundation’s XSEDE initiative and Department Of Energy’s Office of Science. In 2010 he also led one of only 69 teams nationwide to receive an INCITE award (Innovative and Novel Computational Impact on Theory and Experiment) at the Oak Ridge Leadership Computing Facility.

Andrzej Kloczkowski, PhD, is Principal Investigator in the Battelle Center for Mathematical Medicine of the Research Institute at Nationwide Children’s Hospital. He is a Professor of Pediatrics at The Ohio State University College of Medicine. Dr. Kloczkowski’s National Institutes of Health–funded research program focuses on computational structural biology and bioinformatics, including protein structure prediction from the amino acid sequence, prediction of biomacromolecular dynamics using elastic network models, development of coarse grained models and potentials for proteins and nucleic acids, and studies of protein-protein and protein-nucleic acid integrations. He is also interested in application of machine learning methods to various biomedical and clinical problems, and has ongoing collaboration with several experimental and clinical centers.

Jianing Li, PhD, recieved her PhD degree in Chemical Physics from Columbia University in 2011 under the supervision of Professor Richard Friesner. Her dissertation established novel computational approaches for structure-based drug discovery. From 2011 to summer 2014, Dr. Li was working as a postdoctoral researcher in the laboratory of Professor Gregory Voth at The University of Chicago, where her research focused on multiscale modeling and simulations of membrane proteins. In August 2014, Dr. Li started her independent research at the University of Vermont as an assistant professor in chemistry. Dr. Li’s current research focuses on the innovation and applications of multiscale modeling to understand complex chemical systems, aiming to elucidate critical structure-mechanism-function relationships, and to provide rational guide to help drug discovery and materials design. Her research projects include studies of peptide and protein assemblies, protein-sugar interactions, as well as organic, inorganic and hybrid materials, ranging from microscopic (~angstrom, ~nanosecond) to mesoscopic scales (~millimeter, ~millisecond).

Diane Lynch, PhD, received her Bachelor’s/Master’s of Science in Chemistry from Texas A&M University in 1979/1981, respectively. After leaving Texas she continued her education by pursuing a PhD in chemical physics from the California Institute of Technology (1986) in Pasadena, California, and upon graduation she was granted a directors funded postdoctoral appointment at Los Alamos National Laboratory in New Mexico. Upon completion of her postdoctoral studies, she joined the chemistry department at the University of Nevada, Reno as a Research Assistant Professor for 2 years. She spent the next 10 years in industry, including Thinking Machines Corporation, Mobil Central Research, and Pharmacopeia where her role was mainly in algorithm development and computer modeling. In the early 2000’s, she joined the research group of P. Reggio at Kennesaw State University, Kennesaw, Georgia, and after that the University of North Carolina–Greensboro. Her role in the Reggio group has been primarily the application of Molecular Dynamics to the study of the cannabinoid receptors. These receptors are membrane bound proteins sensitive to their environment. Therefore, this requires the simulations of the fully hydrated all-atom phospholipid bilayer. As such, these simulations are compute intensive and thus the group has employed parallel architectures as well as newer hardware, such as graphics processing units (GPUs), in order to obtain results in a timely fashion.

Christopher Rowley, PhD, is an Assistant Professor in the Department of Chemistry at the Memorial University of Newfoundland. Dr. Rowley’s research interests are in computational chemistry, statistical thermodynamics, medicinal chemistry, biophysical chemistry, protein folding, and multi-scale modeling. His research group uses application-driven method development to investigate issues of irreversible enzyme inhibition, ion solvation, and environmental pollutants. Dr. Rowley received his PhD in Chemistry from the University of Ottawa.

Markus Seeliger, PhD, Associate Professor for Pharmacological Sciences and Associate Faculty of the Laufer Center for Computational and Physical Biology at Stony Brook University. The research in my group circles around the questions, how can we help small molecule inhibitors become clinically successful drugs and what can we learn about the molecular regulation of drug targets through their

interaction with small molecule drugs. We combine X-ray crystallography, nuclear magnetic resonance, and other biophysical methods with computational tools.

Lei Shi, PhD, is Chief of the Computational Chemistry and Molecular Biophysics Unit at the National Institute on Drug Abuse Intramural Research Program, National Institutes of Health (NIH). He has a PhD in Pharmacology from Columbia University and completed his postdoctoral training at the Columbia University Medical Center. Before joining NIH, he was an Assistant Professor at Weill Cornell Medical College. Dr. Shi’s research is focused on mechanistic studies of G-protein-coupled receptors and the neurotransmitter transporters, the key targets for pharmacotherapeutic developments for substance use and other neuropsychiatric disorders.

Chung Wong, PhD, received his BSc (Hons.) degree from the Chinese University of Hong Kong and his PhD degree from the University of Chicago. He completed his postdoctoral work with Professor J. Andrew McCammon at the University of Houston. Dr. Wong has held academic and industrial positions at the University of Houston, Mount Sinai School of Medicine, SUGEN, Inc., University of California, San Diego, and the Howard Hughes Medical Institute before joining the faculty of the University of Missouri, St. Louis (UMSL) in 2004. He is currently affiliated with the Department of Chemistry and Biochemistry and the Biochemistry and Biotechnology Program at UMSL. He has performed molecular dynamics simulations on numerous proteins since the 1980s using various computer architectures. He was among the first group of scientists to use explicit-solvent models with periodic boundary conditions, rather than simple distance-dependent dielectric functions, to simulate proteins with molecular dynamics simulations. His group has adapted molecular dynamics simulation to perform free energy calculations, Feynman path integral simulations, sensitivity analysis, and energy flow studies on proteins. His laboratory also uses molecular dynamics simulation extensively to study drug-binding thermodynamics and kinetics.

APPENDIX E

BOARD ON LIFE SCIENCES, BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY,
AND THE NATIONAL ACADEMIES

BOARD ON LIFE SCIENCES

Chair

JAMES P. COLLINS, Arizona State University

Members

A. ALONSO AGUIRRE, George Mason University

ENRIQUETA C. BOND, Burroughs Wellcome Fund

ROGER D. CONE, University of Michigan

NANCY D. CONNELL, Rutgers New Jersey Medical School

JOSEPH R. ECKER, Salk Institute for Biological Studies

SCOTT V. EDWARDS, Harvard University

SARAH C.R. ELGIN, Washington University, St. Louis

ROBERT J. FULL, University of California, Berkeley

ELIZABETH HEITMAN, Vanderbilt University Medical Center

JUDITH KIMBLE, University of Wisconsin–Madison

MARY E. MAXON, Lawrence Berkeley National Laboratory

JILL P. MESIROV, University of California, San Diego

KAREN E. NELSON, J. Craig Venter Institute

CLAIRE POMEROY, Albert and Mary Lasker Foundation

MARY E. POWER, University of California, Berkeley

LANA SKIRBOLL, Sanofi

JANIS WEEKS, University of Oregon

Staff

FRANCES SHARPLES, Director

JO HUSBANDS, Senior Scholar

JAY LABOV, Senior Scholar

LIDA ANESTIDOU, Senior Program Officer

KATIE BOWMAN, Senior Program Officer

KEEGAN SAWYER, Senior Program Officer

AUDREY THEVENON, Program Officer

ANDREA HODGSON, Associate Program Officer

BETHELHEM MEKASHA, Financial Associate

JENNA OGILVIE, Research Associate

ANGELA KOLESNIKOVA, Senior Program Assistant

AANIKA SENN, Senior Program Assistant

BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY

Co-Chairs

DAVID BEM, PPG Industries

JOAN BRENNECKE, NAE, Notre Dame University

Members

MARK BARTEAU, NAE, University of Michigan

MICHELLE V. BUCHANAN, Oak Ridge National Laboratory

JENNIFER SINCLAIR CURTIS, University of California, Davis

RICHARD EISENBERG, NAS, University of Rochester

SAMUEL H. GELLMAN, NAS, University of Wisconsin–Madison

SHARON C. GLOTZER, NAS, University of Michigan

MIRIAM E. JOHN, Sandia National Laboratories (Ret.)

FRANCES S. LIGLER, NAE, University of North Carolina at Chapel Hill and North Carolina State University

JOSEPH B. POWELL, Shell

PETER J. ROSSKY, NAS, Rice University

TIMOTHY SWAGER, NAS, Massachusetts Institute of Technology

Staff

TERESA FRYBERGER, Director

MARILEE SHELTON-DAVENPORT, Senior Program Officer

CAMLY TRAN, Program Officer

ANNA SBEREGAEVA, Associate Program Officer

JESSICA WOLFRAM, Senior Program Assistant

JARRETT NGUYEN, Program Assistant

SHUBHA BANSKOTA, Financial Associate

SUZANNE THILENIUS, Administrative Assistant

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president.

The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president.

The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president.

The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine.

Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task.

Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies.

For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

APPENDIX F

ACKNOWLEDGEMENT OF REPORT REVIEWER

This Consensus Study Report was reviewed in draft form by an individual chosen for his diverse perspective and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individual for his review of this report:

Robert L. Jernigan, Iowa State University

Although the reviewer listed above provided many constructive comments and suggestions, he was not asked to endorse the conclusions or recommendations of this report. In addition, he was responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

APPENDIX G

DISCLOSURE OF CONFLICTS OF INTEREST

The conflict-of-interest policies of the National Academies of Sciences, Engineering, and Medicine generally prohibit an individual from participating in a matter if the individual has a conflict of interest with respect to the matter.

When the committee that authored this Consensus Study Report was established, a determination of whether there was a conflict of interest with respect to any of the proposals to be reviewed by the committee was made for each committee member given the individual’s circumstances and the task being undertaken by the committee. A determination that an individual has a conflict of interest is not an assessment of that individual’s actual behavior or character or ability to act objectively despite the conflicting interest.

The following members of the committee were determined to have a conflict of interest with respect to one or more of the proposals to be reviewed by the committee because of the nature of their relationship with the lead investigator or another member of the research team that submitted the proposal. These committee members were recused from any involvement in the review of the proposals with respect to which they had a conflict.