Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP/H-REMD) for Absolute Ligand Binding Free Energy Calculations.
Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP/H-REMD) for Absolute Ligand Binding Free Energy Calculations.
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DOI：
10.1021/ct1001768
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发表时间：
2010-07-01
影响因子：
5.5
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Roux, Benoit
自由能微扰与复制交换分子动力学（FEP/REMD）为提高自由能计算的收敛性提供了一种强有力的策略。特别是，先前已经表明，允许在热力学耦合参数“lambda”的扩展副本集合内随机移动的FEP/REMD方案可以提高配体与蛋白质的绝对结合自由能计算的统计收敛性[J]。化学。理论计算，2009,5,2583]。在本研究中，FEP/REMD被扩展并与基于哈密顿复制交换MD （H-REMD）的加速MD模拟方法相结合，以克服由于蛋白质受体内存在动力学捕获构象而产生的额外问题。在组合策略中，每个系统在扩展系综中具有给定的热力学耦合因子lambda，进一步与一组在有偏能面上进化的副本耦合，这些副本具有促进势，用于加速结合位点附近侧链不同旋转态之间的相互转换。在扩展的耦合lambda-和H-REMD模拟的双阵列中，允许沿着对应于热力学耦合参数lambda和升压势的轴交替发生交换。该方法是在生物分子模拟程序CHARMM的REPDSTR模块的新扩展基础上实现的。作为示例，计算了T4溶菌酶L99A突变体对二甲苯与非极性腔体的绝对结合自由能。实验表明，双λ - remd和H-REMD模拟方案大大加快了束缚袋周围侧链旋转态的构型采样，从而提高了FEP计算的收敛性。
Free Energy Perturbation with Replica Exchange Molecular Dynamics (FEP/REMD) offers a powerful strategy to improve the convergence of free energy computations. In particular, it has been shown previously that a FEP/REMD scheme allowing random moves within an extended replica ensemble of thermodynamic coupling parameters “lambda” can improve the statistical convergence in calculations of absolute binding free energy of ligands to proteins [J. Chem. Theory Comput. 2009, 5, 2583]. In the present study, FEP/REMD is extended and combined with an accelerated MD simulations method based on Hamiltonian replica-exchange MD (H-REMD) to overcome the additional problems arising from the existence of kinetically trapped conformations within the protein receptor. In the combined strategy, each system with a given thermodynamic coupling factor lambda in the extended ensemble is further coupled with a set of replicas evolving on a biased energy surface with boosting potentials used to accelerate the inter-conversion among different rotameric states of the side chains in the neighborhood of the binding site. Exchanges are allowed to occur alternatively along the axes corresponding to the thermodynamic coupling parameter lambda and the boosting potential, in an extended dual array of coupled lambda- and H-REMD simulations. The method is implemented on the basis of new extensions to the REPDSTR module of the biomolecular simulation program CHARMM. As an illustrative example, the absolute binding free energy of p-xylene to the nonpolar cavity of the L99A mutant of T4 lysozyme was calculated. The tests demonstrate that the dual lambda-REMD and H-REMD simulation scheme greatly accelerates the configurational sampling of the rotameric states of the side chains around the binding pocket, thereby improving the convergence of the FEP computations.
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影响因子：
3.4
作者：
Wang, Jiyao;Deng, Yuqing;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
5.5
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Deng, Yuqing;Roux, Benoit
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2.9
作者：
MORTON, A;MATTHEWS, BW
通讯作者：
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作者：
Mobley, David L.;Chodera, John D.;Dill, Ken A.
通讯作者：
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4.4
作者：
Hamelberg, D;Mongan, J;McCammon, JA
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