New Soft-Core Potential Function for Molecular Dynamics Based Alchemical Free Energy Calculations
New Soft-Core Potential Function for Molecular Dynamics Based Alchemical Free Energy Calculations
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DOI：
10.1021/ct300220p
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发表时间：
2012-07-01
影响因子：
5.5
通讯作者：
de Groot, Bert L.
中科院分区：
文献类型：
--
作者：
Gapsys, Vytautas;Seeliger, Daniel;de Groot, Bert L.
合理的药物设计和蛋白质工程领域受益于基于分子动力学模拟的准确自由能计算。热力学积分常用于通过积分系统哈密顿量相对于耦合参数的变化来计算系统自由能的变化。这些方法利用了热力学循环中的非物理路径，包括粒子的引入和湮灭。这样的炼金术转变需要通过应用软核势能函数来避免奇点，从而修改经典的非键势能项。在这项工作中，我们提出了一种用于非平衡自由能计算的软核势的新公式，该公式缓解了所有中间炼金术状态下所有非键相互作用的所有组合的势能的奇异性、数值不稳定性和额外的最小值。该方法被应用于(A)封闭热力学循环的自由能计算，(B)突变对蛋白质热稳定性的影响，(C)小配体挽救自由能的计算，和(D)胰酶抑制剂结合自由能的估计。结果表明，新的软核函数为炼金术自由能计算提供了一种稳健、准确的通用解决方案。
The fields of rational drug design and protein engineering benefit from accurate free energy calculations based on molecular dynamics simulations. A thermodynamic integration scheme is often used to calculate changes in the free energy of a system by integrating the change of the system's Hamiltonian with respect to a coupling parameter. These methods exploit nonphysical pathways over thermodynamic cycles involving particle introduction and annihilation. Such alchemical transitions require the modification of the classical nonbonded potential energy terms by applying soft-core potential functions to avoid singularity points. In this work, we propose a novel formulation for a soft-core potential to be applied in nonequilibrium free energy calculations that alleviates singularities, numerical instabilities, and additional minima in the potential energy for all combinations of nonbonded interactions at all intermediate alchemical states. The method was validated by application to (a) the free energy calculations of a closed thermodynamic cycle, (b) the mutation influence on protein thermostability, (c) calculations of small ligand salvation free energies, and (d) the estimation of binding free energies of trypsin inhibitors. The results show that the novel soft-core function provides a robust and accurate general purpose solution to alchemical free energy calculations.