accelerated Molecular Dynamics (amd) Tutorial Levi Pierce 2012 NBCR Summer InsAtute

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1 accelerated Molecular Dynamics (amd) Tutorial Levi Pierce 2012 NBCR Summer InsAtute

2 Time Scales Accessible with Molecular Dynamics Pierce, L.C.T.; Salomon- Ferrer, R.; de Oliveira C.A.; McCammon, J.A.; Walker, R.C.; RouAne Access to Millisecond Timescales with Accelerated Molecular Dynamics. in press 2

3 Molecular Dynamics Δt... Δt Ensemble of structures McCammon J. A., Gelin, B. R., Karplus M. Nature 267, 585 (1977) 3

4 MoAvaAon Why do we need to accelerate molecular dynamics? Can we just increase our Ame step used for integraaon? Can we just heat our system up?

5 Accelerated Molecular Dynamics Add a bias to our potenaal energy surface to promote escape from energeac traps. EquaAon as applied to total potenaal energy!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! The corrected canonical ensemble average of a given property, <A> c can be obtained by reweighang each point in the configuraaon space on the modified potenaal by the strength of the Boltzmann factor of the bias energy, exp(βδv(r, t i )) 5

6 LimitaAons of amd In 2008 code was not efficiently parallelized Sander amd implementaaon is slow BPTI Simula<on 17,758 Atoms ns/day Number of Processors sander amd How can we accelerate amd? Port method to faster codes (pmemd,namd) Use Graphics Processing Units (GPUs) 6

7 ComputaAon on the GPU Why are they so fast? Lots of relaavely fast workers vs a few fast workers Cluster (48 processors operaang at 2.6GHz) 30ns/day 1GTX 580 (512 processors operaang at 770MHz) 40ns/day Why are they so popular now? Compute Unified Design Architecture (CUDA) GPU molecular dynamics codes ACEMD hkp://mulascalelab.org/acemd OPENMM hkps://simtk.org/home/openmm AMBER (pmemd.cuda) hkp://ambermd.org/gpus/ NAMD hkp:// 7

8 ImplemenAng amd on the GPU First ported sander amd to pmemd Next ported amd to pmemd.cuda 1 GTX ns/day cmd 1 GTX ns/day amd How fast can we run amd? 2 GTX ns/day amd How can we validate our implementaaon? ns/day ns/day ns/day BPTI 17,758 atoms NVT Number of of Processors Number of Processors PMEaMD PMEaMD PMEaMD sander amd sander amd sander amd GTX580 amd NAMD amd GTX580 amd Lindert, S.; Kekenes- Huskey, P.; Huber, G.; Pierce, L.C.T.; McCammon, J.A.; Dynamics and Calcium AssociaAon to the N- Terminal Regulatory Domain of Human Cardiac Troponin C: A MulA- Scale ComputaAonal Study. J. Chem. Phys. B Wang, Y., et. al., ImplementaAon of Accelerated Molecular Dynamics in NAMD. Computa,onal Science & Discovery,

9 Protocol Outline Run convenaonal molecular dynamics unal dihedral and total potenaal energy are converged usually 10-50ns is all that is needed Compute the Ecut and alpha needed for boosang dihedral potenaal Compute Ecut and alpha needed for boosang total potenaal Fire off amd simulaaon!

10 Amber12 BPTI Example Step 1 Running ConvenAonal Molecular Dynamics (cmd) I generally run 10ns of NVT dynamics and then look at the output log for the average total potenaal energy and dihedral energy You can also grep EPtot and DIHED out from your log file and compute the averages A V E R A G E S O V E R S T E P S NSTEP = TIME(PS) = TEMP(K) = PRESS = 0.0 Etot = EKtot = EPtot = BOND = ANGLE = DIHED = NB = EEL = VDWAALS = EELEC = EHBOND = RESTRAINT =

11 Amber12 BPTI Example Step 2 Compute EthreshP and alphap First calculate alphap from the total number of atoms alphap= (0.16kcal mol - 1 atom - 1 * 18,226 atoms) = 2916 kcal mol - 1 To calculate EthreshP you need the average Eptot and the total number of atoms in your system EthreshP= kcal mol alphap = kcal mol - 1 Grant, B. J.; Gorfe, A. A.; McCammon, J. A., Ras conformaaonal switching: simulaang nucleoade- dependent conformaaonal transiaons with accelerated molecular dynamics. PLoS Comput. Biol. 2009, 5, (3), e de Oliveira, C. A. F.; Grant, B. J.; Zhou, M.; McCammon, J. A., Large- Scale ConformaAonal Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics SimulaAon. PLoS Comput. Biol. 2011, 7, (10), e

12 Amber12 BPTI Example Step 3 Compute EthreshD and alphad First calculate alphap from the total number of solute residues alphad= (1/5)*(4kcal mol - 1 residue - 1 * 58 solute residues) = 827 kcal mol - 1 To calculate EthreshD you need the average DIHED and the total number of solute residues in your system EthreshD= 595 kcal mol (4kcal mol - 1 residue - 1 * 58 solute residues) = 46.4 kcal mol - 1 Grant, B. J.; Gorfe, A. A.; McCammon, J. A., Ras conformaaonal switching: simulaang nucleoade- dependent conformaaonal transiaons with accelerated molecular dynamics. PLoS Comput. Biol. 2009, 5, (3), e de Oliveira, C. A. F.; Grant, B. J.; Zhou, M.; McCammon, J. A., Large- Scale ConformaAonal Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics SimulaAon. PLoS Comput. Biol. 2011, 7, (10), e

13 Amber12 BPTI Example Step 4 Run amd SimulaAon! For the GPU version simply run pmemd.cuda - O - i amd.in - o amd1.out - r amd1.rst - x amd1.nc - p bpa.prmtop - c eq.rst For the effeciently parallelized CPU version run mpirun - np NPROCS pmemd.mpi - O - i amd.in - o amd1.out - r amd1.rst - x amd1.nc - p bpa.prmtop - c eq.rst For the inefficient CPU version run mpirun - np NPROCS sander.mpi - O - i amd.in - o amd1.out - r amd1.rst - x amd1.nc - p bpa.prmtop - c eq.rst amd.in (NVT- CONTINUE) &cntrl imin=0,irest=1,ntx=5, nstlim= ,dt=0.002, ntc=2,nv=2,ig=- 1, cut=10.0, ntb=1, ntp=0, ntpr=1000, ntwx=1000, nk=3, gamma_ln=2.0, temp0=300.0,iouvm=1, iamd=3,iwrap=1, EthreshD=827, alphad=46.4,ethresp= , alphap=2916, /

14 Examining Results How do we observe more sampling from amd compared to MD? PhiPsi plots of dihedral angles RMSD Principal Component Analysis

15 ReweighAng Using the true exponenaal Alanine DipepAde Using approximaaons to the exponenaal BPTI

16 Useful links hkp://ambermd.org/gpus/ amd on NAMD hkp:// ug/node63.html