Computational Biophysics - BioInfoSummer 2012 (Jason Roberts)

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Case Study: Atomistic Molecular Dynamics Simulations of Poliovirus

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Computational Biophysics - BioInfoSummer 2012 (Jason Roberts)

  1. 1. Case Study: Atomistic Molecular Dynamics Simulation of PoliovirusJason A. Roberts, Senior Medical Scientist,National Enterovirus Reference Laboratory,WHO Regional Poliomyelitis Reference Laboratory, VIDRLApplied Sciences, RMIT University, Australia.
  2. 2. Animation – Creates the illusion of movementSimulation – Tool for testing a hypothesis
  3. 3. Study of a molecule(s) structure and functionusing computational methods such as: Semi-empirical quantum mechanics Atomistic Molecular Dynamics Coarse-Grained Molecular Dynamics Hybrid methodsUltimately these are just models!
  4. 4. Supercomputer Peak Speed (RMax) vs Time (years)100,000.00 10,000.00 Cray Titan 17.59 PFLOPS 1,000.00 First 1µs simulation of enzyme folding (BPTI) 10,000 atoms (4 months) 100.00 Rmax (TFLOPS) 10.00 4U Server + 8GPU 3.3 million atom poliovirus or TFOLPS rhinovirus 1µs simulation Desktop + GPU (4 months) Eg. Avoca VLSCI 2012 1.00 BlueGene/Q using 25% of RMax 0.10 iPhone 0.01 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 Year
  5. 5. BlueGene/Q (VLSCI@25%) = 8.9 days 65,536 threads (~172 TFLOPS)BlueGene/P = 3 months 2048 cores (~7 TFLOPS)4u GPU Server (CUDA) = 3 months 32cores + 8GPUs (~10.5 TFLOPS)Desktop GPU (CUDA) = 1 year 12core + 2GPU (~2.2 TFLOPS)Modern Laptop = 20 years 4core i7 (~0.15 TFLOPS)iPhone, Android = 300 years (~0.01 TFLOPS)
  6. 6. Side-chain behaviour Hydrophobicity Variations in pH conditions Side-chain to side-chain interactions eg. S-S bonds in CysteineSalt BridgesLong-range electrostatics (eg. PME)
  7. 7. Nucleic Magnetic Resonance Small structures, very high resolution. Provides some conformational state dataX-ray crystallography High resolution Requires production of a crystalCryogenic Electron Microscopy Biologically representative, relatively low resolution
  8. 8. Based on existing data attained by traditionalmethods eg: Nuclear Magentic Resonance (<1.0 Å) X-ray crystallography (0.5-10 Å) most ~2.0 Å Cryo-EM (~4-20 Å)Able to simulate various biologicalenvironmentsPlace a static structure in a simulatedbiological environment
  9. 9. X-Ray Crystal NMR CryoEM
  10. 10. PubMed search Polio – 22,922 (c1879 onwards) Poliovirus – 14,381 (c1951 onwards) Picornavirus – 30,708 (c1945 onwards)RCSB records – Poliovirus (56) – Picornaviridae (207) - 41 X-Ray - 180 X-Ray - 8 EM - 19 EM - 7 NMR - 8 NMR
  11. 11. Optimal match selected manually from RCSB-Protein Data Bank and phylogenetic analysisModels created using SWISS-Model with template1HXS (2.2 angstrom resolution, most completechain information)Matrix data used from template to recreate fullcapsid using VMD multiseq for 3D alignment andmon2poly script to generate new chainsCustom parameter files generated usingSwissParam website
  12. 12. Figure derived from Fields Virology 6th edition and Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  13. 13. Quantum mechanics Realistic throughput of ~100 atoms Ab-initio modelling (eg. protein folding) μs – ms timeframe with multiple conformations = very unreliable and computationally expensive. Homology Modelling 30% 60% 90% 100% Unreliable OK – Careful checking Good - Reliable Excellent% Amino Acid Identity
  14. 14. Virus reconstruction 241 protein chains (52,812 Amino Acids) 120 lipids (60 covalent bonded to N-terminus VP4) 7.5 kb RNA genome Total virus model >1 million atoms Simulation size 4.2 million atoms (Cubic PBC) More than 3 million water atoms and ions! ~15-40 million CPU hours to simulate 1μs!
  15. 15. Rhombic dodecahedron 3.3 Million atoms Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  16. 16. Topology file generationIon placementData transfer and analysis Files for creation, simulation and analysis ▪ 0.1μs simulation time = 50GB of files (0.1ns steps) Simple calculations (RMSD/F) for protein coat ▪ 10ns trajectory data at 0.1ns time points ▪ 52,800 amino acids x 100 intervals ▪ 5.28 million data points Excel spread sheets need not apply
  17. 17. Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  18. 18. Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  19. 19. Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  20. 20. A. Pentamer B. Empty Capsid C. Full Virus Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  21. 21. A. Empty Capsid B. Full Virus Figure derived from Roberts, JA ., et al DOI 10.1016/j.jmgm.2012.06.009
  22. 22. exaFLOP (1018) computingBetter scaling via architecture and softwareimprovementspetaFLOP = >10ns/day full virusexaFLOP ~= >10μs/day full virusSimulations approaching billions of atomsNewer force fields to emulate quantummechanicsIncreased integration of MD in research
  23. 23. A/Prof. Bruce Thorley - VIDRLDr. Mike Kuiper - VLSCIDr. Andrew Hung - RMIT UniversityProf. Peter Smooker - RMIT UniversityWHO Regional Poliomyelitis Reference Lab Tom Aitken Aishah Ibrahim Linda Hobday

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