James Phillips Beckman Institute, University of Illinois - PowerPoint PPT Presentation

Attacking HIV with Petascale Molecular Dynamics Simulations on Titan and Blue Waters James Phillips Beckman Institute, University of Illinois http://www.ks.uiuc.edu/Research/namd/ Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

NIH Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics Developers of the widely used computational biology software VMD and NAMD 250,000 registered VMD users research projects include: virus Renewed 2012-2017 80,000 registered NAMD users capsids, ribosome, photosynthesis, protein folding, membrane reshaping, with 10.0 score (NIH) animal magnetoreception 600 publications (since 1972) over 54,000 citations Achievements Built on People 5 faculty members 8 developers 1 systems administrator 17 postdocs 46 graduate students 3 administrative staff Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Tajkorshid, Luthey-Schulten, Stone, Schulten, Phillips, Kale, Mallon Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Related talks (to stream) • S6623 - Advances in NAMD GPU Performance • Antti-Pekka Hynninen, Oak Ridge National Laboratory • S6253 - VMD: Petascale Molecular Visualization and Analysis with Remote Video Streaming • John Stone, University of Illinois at Urbana-Champaign Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 3 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Need for petascale: Simulation follows structural discovery 10 8 HIV capsid 10 7 Number of atoms Ribosome 10 6 STMV ATP Synthase 10 5 ApoA1 Lysozyme 10 4 1986 1990 1994 1998 2002 2006 2010 2014 Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Structural Route to the HIV-1 Capsid 1st TEM (1999) 1st tomography (2003) crystal structures of separated hexamer and pentamer Ganser et al. Science , 1999 Pornillos et al. , Cell 2009 , Nature 2011 Briggs et al. EMBO J , 2003 Briggs et al. Structure , 2006 High res. EM of hexameric tubules, tomography of cryo-ET (2006) capsids, all-atom model of capsid by MDFF hexameric tubules Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Li et al., Nature , 2000 Byeon et al., Cell 2009 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu Zhao et al. , Nature 497: 643-646 (2013)

Capsid shepherds HIV RNA inside the cell Capsid Binding Fusion uncoating Host Cell Nuclear Import Integration Virion into the host’s chromatin Budding Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

How is HIV treated today? Fusion/Entry inhibitors Currently no drug targets capsid uncoating or Host Cell nuclear import ! Reverse Transcription (RNA to DNA) inhibitors Integrase inhibitors Protease inhibitors Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

HIV capsid contains 186 hexamers, 12 pentamers, 1300+ proteins, 4.2 million atoms

Malleability of HIV-1 CA Hexamer of hexamers bite angles along chiral axis 1300 proteins in different conformations hexamers pentamers Native capsid bite angle distribution G. Zhao, et al. Nature 497 (2013)

One-Microsecond Simulation Includes 64 Million Atoms Key person: Juan Perilla (UIUC)

Capsid acts as an osmotic regulator Results from 64 M atom, 1 µs molecular dynamics simulation! Chloride ions permeate through the hexameric center

Curvature is regulated by the trimer interface at the atomic level A204 I201 E213 K203 HIV-CA wild-type in vitro A204C mutant in vitro Nature 497 , 643-646 G. Zhao, et al. Nature 497 (2013) Peijun Zhang - U. Pittsburgh

HIV uncoating relies on cell factor Cyclophilin A Binding Infection of cypA of nucleus Outside cypA binding pattern prevents TRIM binding, of Cell but leaves nuclear pore interactions intact Cell Nucleus TRIM Binding Premature of E2 uncoating lattice No infection F. Diaz-Griffero, Viruses (2011)

Simulation reveals how CypA stabilizes capsid only polarizable force field yields stable bridge interaction interaction confirmed by NMR

Chemical Detail is Essential to Capsid Function A204 I201 E213 K203 Ions permeate through the capsid. Curvature regulated In preparation. by trimeric interface. Nature, 497 643-646 Pfizer PF74 inhibits HIV-1 infection at an early step during infection. CypA bridges Journal of Physical Chemistry Letters, adjacent capsid subunits accepted Nature Communications, 7 10714

HIV Acknowledgments Juan R. Perilla Klaus Schulten Peijun Zhang Angela M. Gronenborn Theoretical and Computational Biophysics Group Department of Structural Biology Center for HIV Protein Interactions University of Pittsburgh School of Medicine University of Illinois at Urbana-Champaign Christopher Aiken Department of Pathology Laxmikant Kale and Immunology Parallel Programming Lab Vanderbilt University Dept. of Computer Science School of Medicine Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Beyond Viruses: Modeling the Bacterial Brain MDFF produces optimal overlap with EM data “Dock” array models into EM density Chemosensory Array Core-signaling Unit (PDB: 3JA6) Cassidy, C. K. et al. "CryoEM and computer simulations reveal a novel kinase conformational switch in bacterial chemotaxis signaling." eLife 4 (2015): e08419.

Beyond Large: Complete Description of Transport Cycle via Bias-Exchange Umbrella Sampling (Moradi, Tajkhorshid) OF apo IF apo out out in in out out apo +substrate in in OF bound IF bound Law,% et#al. ,% Biochemistry# 46 ,%12190%(2007).% M. Moradi, G. Enkavi, and E. Tajkhorshid (2015) Nature Communications, 6:8393.

Beyond Illinois: Influenza Virus Coat, Amaro Lab, UCSD http://www.ncsa.illinois.edu/news/story/blue_waters_enables_massive_flu_simulations

GPUs are critical for visualization and analysis Large memory GPU-accelerated workstations can be accessed remotely from our facility today, but for future machines must be embedded at supercomputer centers . Compressed Video 1 Gigabit Network Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Remote Visualization Now • TACC Stampede supports this today – Includes nodes with 1TB memory – Not virtualized, allocate full dedicated node – New Maverick cluster added • Blue Waters – no visualization resource • Titan – Rhea adds large-memory GPU nodes • NIH Center - using NICE DCV for remote access Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

NAMD is based on Charm++ Complete info at charmplusplus.org Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Charm++ Used by NAMD • Parallel C++ with data driven objects. • Asynchronous method invocation. • Prioritized scheduling of messages/execution. • Measurement-based load balancing. • Portable messaging layer. Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

NAMD Hybrid Decomposition Kale et al., J. Comp. Phys. 151:283-312, 1999. • Spatially decompose data and communication. • Separate but related work decomposition. • “Compute objects” facilitate iterative, measurement-based load balancing system. Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

NAMD Overlapping Execution Phillips et al., SC2002 . Offload to GPU Objects are assigned to processors and queued as data arrives. Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu

Overlapping GPU and CPU with Communication GPU Remote Force Local Force f f x x CPU Remote Local Local Update f x f x Other Nodes/Processes One Timestep Phillips et al., SC2008 Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics GTC 2016 Beckman Institute, University of Illinois at Urbana-Champaign - www.ks.uiuc.edu