生物大分子构象采样方法与自由能计算课件

陈长军,2016. 6,生物大分子构象采样与自由能计算,1,华中科技大学物理学院,2,副本交换采样方法,I. 主流动力学采样方法,二、偏倚采样,一、非偏倚采样,Adaptively Biased Molecular Dynamics,Adaptive Biasing Force,Metadynamics,Umbrella Sampling Method,Replica Exchange Molecular Dynamics,Simulated Annealing,3,势函数，坐标数，迭代方式,J. Chem. Phys., Vol. 112, 1 2000,J. Chem. Phys., Vol. 118, 1 2003,J. Chem. Phys., Vol. 109, 8 1998,三、约束动力学采样,4,II.副本交换采样方法,微软学术搜索,5,6,Phase space (r, p),Potential,T1,T2,Z.W.Ulissi http:/www.rikenresearch.riken.jp/eng/frontline/6290),副本可以在哈密顿空间或温度空间排列,时间,7,Sugita, Y.; Okamoto, Y. Chem Phys Lett 1999, 314, 141-15,Replica Exchange Molecular Dynamics (1999),Parallel Tempering (1997),Hansmann, U. H. E. Chem Phys Lett 1997, 281, 140-150,8,副本交换方法的效率取决于两点：,单副本采样时间，多副本交换频率,replica 3,replica 2,replica 1,9,多副本交换频率,单副本采样时间,分段REMD模拟,Time,Temperatures,Simulated tempering (1992),Marinari, E.; Parisi, G. Europhys Lett 1992, 19, 451-458 Rosta, E.; Hummer, G. J Chem Phys 2010, 132, 034102.,10,11,Okur, A.; Roe, D. R.; Cui, G.; Hornak, V.; Simmerling, C. J Chem Theory Comput 2007, 3, 557-568.,reservoir REMD (2007),Simulation time? Temperature?,Li, Y.; Protopopescu, V. A.; Arnold, N.; Zhang, X.; Gorin, A. Appl Math Comput 2009, 212, 216-228,12,Hybrid PT/SA (2009),replica 3,replica 2,replica 1,13,Infinite swapping (2011),Plattner, N.; Doll, J. D.; Dupuis, P.; Wang, H.; Liu, Y.; Gubernatis, J. E. J Chem Phys 2011, 135(13), 134111,14,Infinite swapping (2011),Plattner, N.; Doll, J. D.; Dupuis, P.; Wang, H.; Liu, Y.; Gubernatis, J. E. J Chem Phys 2011, 135(13), 134111,Terms in xyz: N!,N! =40320,15,直接引入非活跃副本（inactive replica）,III.我们的工作,16,检验分布函数 （量子谐振子，3 replicas VS. 10 replicas）,T=5.0 toT=1000.0,n=0 to n=9,n=0 to n=9,17,检验分布函数（丙氨酸二肽 3 replicas VS. 7 replicas）,T=300, 353, 416, 489, 576, 679 and 800K,18,性能比较 （Ising模型）,T=1.4,reduced magnetization,19,T=1.4 to 1.8,不同数目的活跃副本在固定的8个温度上模拟,REMD,Simulated Tempering,our method,性能比较 （Ising模型）,20,T=1.4 to 1.8,2个活跃副本在不同数目的温度上模拟,性能比较 （Ising模型）,自由能计算误差,21,实际表现（Trpzip2发卡）,Chen, C. and Y. Xiao, Observation of multiple folding pathways of -hairpin trpzip2 from independent continuous folding trajectories. Bioinformatics, 2008. 24: 659-665.,22,12个副本12个温度,6个副本6个温度,6个副本16个温度,23,温度空间分布函数比较,能量空间分布函数比较,24,能量函数,热熔函数,自由能函数,25,1 Chen, C. and Y. Huang, Walking freely in the energy and temperature space by the modified replica exchange molecular dynamics method. J. Comput. Chem., 2016. 37: 1565-1575. 2 Chen, C., Y. Xiao, and Y. Huang, Improving the replica-exchange molecular-dynamics method for efficient sampling in the temperature space. Phys. Rev. E, 2015. 91: 052708.,相关文章,26,27,自由能计算与路径优化,J. Chem. Phys., Vol. 112, 1 2000,J. Chem. Phys., Vol. 118, 1 2003,J. Chem. Phys., Vol. 109, 8 1998,28,I. 约束动力学方法,J. Schlitter and M. Klahn, Mol. Phys. 101, 3439 (2003).,反应坐标 集合坐标 笛卡尔坐标,单值问题？ 连续可微问题？,H=(1- )H1 + H2,30,Chen, C., Y. Huang, and Y. Xiao, Free-energy calculations along a high-dimensional fragmented path with constrained dynamics. Phys. Rev. E., 2012. 86(3-1): 031901,31,Ala dipeptide,32,in vacuum,in implicit solvent,33,constrained simulation,restrained simulation,II.优化反应路径,A. Ulitsky and R. Elber, J. Chem. Phys. 92, 1510 (1990),34,SDP,saddle point,SDP,MEP,MFEP,35,SDP,saddle point,SDP,string method, 2006,Maragliano, L.; Fischer, A.; Vanden-Eijnden, E.; Ciccotti, G. J Chem Phys 2006, 125, 024106.,36,36,one-the-fly string model, 2007,Maragliano, L.; Vanden-Eijnden, E. Chem Phys Lett 2007, 446, 182-190.,我们的方法：势能面优化 + 最速下降 + 约束动力学,37,Chen, C., Y. Huang, X. Ji, and Y. Xiao. Efficiently finding the minimum free energy path from steepest descent path. J. Chem. Phys. 2013. 138:164122,38,39,丙氨酸十肽,40,快速优化 - 断层扫描方法,Chen, C., Y. Huang, W. Jiang, and Y. Xiao, A fast tomographic method for searching the minimum free energy path. J. Chem. Phys., 2014. 141: 154109,丙氨酸二肽,Ace-GGPGGG-Nme peptide,cubic B-spline,Adaptively Biased Molecular Dynamics,kernel,V. Babin, C. Roland, and C. Sagui, J. Chem. Phys. 2008, 128: 134101,41,路径优化,42,Chen, C., Y. Huang, W. Jiang, and Y. Xiao, A fast tomographic method for searching the minimum free energy path. J. Chem. Phys., 2014. 141: 154109,21 snapshots,43,the fast tomographic method (solid lines, path 1, 4, 10) vs constrained method (dashed lines, path 0, 100, 200 and 300),Chen, C., Y. Huang, W. Jiang, and Y. Xiao, A fast tomographic method for searching the minimum free energy path. J. Chem. Phys., 2014. 141: 154109,丝氨酸二肽,丝氨酸二肽,21 snapshots,45,free energy surfaces for the 12th (a), 14th (b), 16th (c) and 18th (d) snapshots,fast tomographic method (solid lines, path 1, 4, 10) ) vs constrained method (dashed lines, path 0, 100, 200 and 300),46,fast tomographic method (solid lines, path 1, 4, 10) vs constrained method (dashed lines, path 0, 100, 200 and 300),47,III.局部自由能计算,1) 单点计算,2) 全空间采样,3) 沿特定路径计算,4) 局部计算,48,改进的SHAKE和RATTLE约束动力学方法,Chen, C., Calculation of the local free energy landscape in the restricted region by the modified tomographic method. J. Phys. Chem. B, 2016. 120: 3061-3071,49,丝氨酸二肽,实际测试,50,苏氨酸,1 Chen, C., Calculation of the local free energy landscape in the restricted region by the modified tomographic method. J. Phys. Chem. B, 2016. 120: 3061-3071. 2 Chen, C., Y. Huang, W. Jiang, and Y. Xiao, A fast tomographic method for searching the minimum free energy path. J. Chem. Phys., 2014. 141: 154109. 3 Chen, C., Y. Huang, X. Ji, and Y. Xiao, Efficiently finding the minimum free energy path from steepest descent path. J. Chem. Phys., 2013. 138: 164122. 4 Chen, C., Y. Huang, X. Jiang, and Y. Xiao, Binding free-energy calculation of an ion-peptide complex by constrained dynamics. Phys. Rev. E., 2013. 87: 062705. 5 Chen, C., Y. Huang, and Y. Xiao, Free-energy calculations along a high-dimensional fragmen