显式溶剂化条件下协调水化自由能估算的炼金术变换
Alchemical Transformations for Concerted Hydration Free Energy Estimation with Explicit Solvation
摘要：
我们提出了一个家庭的炼金术扰动势，使小到中等大小的分子的水合自由能的计算在一个协调一致的单一炼金术耦合步骤，而不是常用的序列的两个不同的耦合步骤的Lennard-Jones和静电相互作用。扰动势是基于溶质-溶剂相互作用能的softplus函数，其设计用于沿着炼金术途径在熵瓶颈附近集中采样。我们提出了一个通用的框架来优化这类炼金术微扰势的参数。优化过程是基于$λ$ -函数形式主义和最大似然参数估计程序，我们开发的早期，以避免发生沿炼金术路径的耦合能的多峰分布。因为它不需要修改的核心力和能量例程，软核配方可以很容易地部署在分子动力学模拟代码。我们说明的方法，通过将其应用到不同大小和复杂性的化合物的水滴中的水合自由能的估计。在每种情况下，我们表明，收敛的水化自由能迅速实现。这项工作铺平了道路，正在进行的开发更精简的算法来估计分子结合的自由能与明确的溶剂化。
英文摘要：
We present a family of alchemical perturbation potentials that enable the calculation of hydration free energies of small to medium-sized molecules in a concerted single alchemical coupling step instead of the commonly used sequence of two distinct coupling steps for Lennard-Jones and electrostatic interactions. The perturbation potentials are based on the softplus function of the solute-solvent interaction energy designed to focus sampling near entropic bottlenecks along the alchemical pathway. We present a general framework to optimize the parameters of alchemical perturbation potentials of this kind. The optimization procedure is based on the $λ$-function formalism and the maximum-likelihood parameter estimation procedure we developed earlier to avoid the occurrence of multi-modal distributions of the coupling energy along the alchemical path. A novel soft-core function applied to the overall solute-solvent interaction energy rather than individual interatomic pair potentials critical for this result is also presented. Because it does not require modifications of core force and energy routines, the soft-core formulation can be easily deployed in molecular dynamics simulation codes. We illustrate the method by applying it to the estimation of the hydration free energy in water droplets of compounds of varying size and complexity. In each case, we show that convergence of the hydration free energy is achieved rapidly. This work paves the way for the ongoing development of more streamlined algorithms to estimate free energies of molecular binding with explicit solvation.
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