Application of the Markov State Model to Molecular Dynamics of Biological Molecules. Speaker: Xun Sang-Ni Supervisor: Prof. Wu Dr.

Transcription

1 Application of the Markov State Model to Molecular Dynamics of Biological Molecules Speaker: Xun Sang-Ni Supervisor: Prof. Wu Dr. Jiang

2 Introduction Conformational changes of proteins : essential part of many biological processes Protein folding Ligand binding Signal transduction Enzymatic catalysis Allosteric regulation

3 Introduction Molecular dynamics simulations can describe the dynamics of molecules at atomic level Anton MD mechine

4 Introduction Problem1: Timescale (conventional MD methods) are limited Rugged energy surface in high dimensional system

5 Enhanced sampling method : Replica exchange MD Targeted MD Steered MD Metadynamics MD Introduction Available tools to solve Problem1: Reaction coordinates (RMSD, Q, Rg) Markov State Model Free energy surface Robert DM et al, Da LT, Sheong FK, Silva DA, Huang X, Adv Exp Med Biol, 2014, 805:

6 What is Markov State Model Markov Chain Definition: A discrete time stochastic process X 0, X 1, X 2, is a Markov chain if: Pr (X t = a t X t-1 = a t-1, X t-2 = a t-2,,x 0 = a 0 ) = Pr(X t = a t X t-1 = a t-1 ) Andrey Markov Russian mathematician a 0 a 1 a t-1 a t t-3 t-2 t-1 t Time Michael Mitzenmacher, Probability and Computing, 2005, Pr(X t = a t X t-1 = a t-1 )

7 What is Markov State Model t P t-1 ij j i P ij = Pr(X t = j X t-1 = i) B 0.5 A C A simple example: 3 state model Time P A P B P C

8 What is Markov State Model t P t-1 ij j i P ij = Pr(X t = j X t-1 = i) 0.5 A simple example: 3 state model A Time P A P B P C B 0.0 C τ P A p P B P AA p BA C p CA P A = 1 x x x 0.3 = 0.5 P B = 1 x x x 0.3 = 0.3 P = 1 x x x 0.4 = 0.2

9 What is Markov State Model P ij = Pr(X t = j X t-1 = i) A simple example: 3 state model 0.5 Time P A P B P C A B C τ τ P A p P B P AA p BA C p CA P A = 0.5 x x x 0.3 = 0.37 P B = 0.5 x x x 0.3 = 0.45 P C = 0.5 x x x 0.4 = 0.18

10 What is Markov State Model 0.5 A A simple example B C

11 What is Markov State Model 0.5 A A simple example B C

12 What is Markov State Model A simple example

13 Michael Mitzenmacher, Probability and Computing, 2005, What is Markov State Model Markov Chain Definition: A discrete time stochastic process X 0, X 1, X 2, is a Markov chain if: Pr (X t = a t X t-1 = a t-1, X t-2 = a t-2,,x 0 = a 0 ) = Pr(X t = a t X t-1 = a t-1 ) P 0,0 P 0,2 P 0,j t P t-1 ij i P ij = Pr(X t = j X t-1 = i) j One-step transition matrix = P 1,0 P 1,1 P 1,j P i,0 P t,1 P i,j

14 Application of MSM to MD simulation Markov State Model MD simulation Transition modes between different states A discrete time process Independent of the history before the last step t-1 t (p, q) (p, q)

15 Application of MSM to MD How can MSM be applied to MD? MSM builder Prof. Vijay S pande

16 Application of MSM to MD 1. Enhanced sampling How can MSM be applied to MD? Eg. Targeted MD Noé F, Fischer S, Curr Opin Struct Biol, 2008, 18(2):

17 Application of MSM to MD How can MSM be applied to MD? 2. Geometric clustering for seeding K-center, K-means

18 Application of MSM to MD How can MSM be applied to MD? 3. Unbiased short MD simulations initiated from the seeds clusterd M clusters M trajectories

19 Application of MSM to MD How can MSM be applied to MD? 4. Geometric clustering for microstates K-center, K-means N trajectories N microstates

20 Application of MSM to MD How can MSM be applied to MD? 5. Building the transition count matrix (Transition probability matrix) From/to State 1 State N 11 =1 N 12 =4 N 21 =3 N 22 =2 State State From/to State 1 State 2 State State From/to State 1 State 2 State State Da LT, Sheong FK, Silva DA, Huang X, Adv Exp Med Biol, 2014, 805:

21 Application of MSM to MD How can MSM be applied to MD? 5. Building the transition probability matrix P(nτ) is a vector of microstate populations at time nτ Da LT, Sheong FK, Silva DA, Huang X, Adv Exp Med Biol, 2014, 805:

22 Application of MSM to MD How can MSM be applied to MD? 6. Lumping microstates into microstates. Perron cluster cluster analysis PCCA microstates macrostates Da LT, Sheong FK, Silva DA, Huang X, Adv Exp Med Biol, 2014, 805:

23 Application of MSM to MD Da LT, Sheong FK, Silva DA, Huang X, Adv Exp Med Biol, 2014, 805: Li SS et al, J. Chem. Theory Comput, 2014, 10(6): Analysis of markov state model How can MSM be applied to MD? The 10 most populated macrostates from the coarsegrained MSM with their equilibrium populations The top 15 folding fluxes Transition pathway theory

24 Advantages of MSM Enhanced sampling + multi-parallel short conventional MD simulations No specified reaction coordinates (clustering) Thermodynamic information Equilibrium populations Kinetic information Dominant pathways

25 Cautions of MSM Sufficiency sampling is still challenging Accurate force fields Connections to experiments Pande VS et al, Methods, 2010, 52(1):

26 Popularity of MSM Key word = markov state model + molecular dynamics simulation

27 Popularity of MSM Recent notable work Prof. Huang Xuhui Dr. Da Lintai

28 Summary Markov state model is a mathematical model applied to molecular dynamic simulations Large timescale equilibrium simulations Clustering (Higher dimensional data ) Thermodynamic information (equilibrium populations) Kinetic information ( dominant pathways) Increasing popularity