用于溶剂化自由能计算的集成炼金术与构象增强采样方法
Integrated Alchemical and Conformational Enhanced Sampling for Solvation Free Energy Calculations
AI总结：
该研究开发了集成λ-动力学、OPES与d-AFED的增强采样协议，提升了溶剂化自由能计算的精度与效率，为复杂体系的炼金术自由能方法应用奠定基础。
AI中文摘要：
从分子动力学模拟获得准确的溶剂化自由能，需要对耦合的慢变量进行高效采样，包括溶剂坐标、溶质构象模式以及炼金术坐标λ。本文开发了一种λ-动力学框架，其结合了质量缩放、实时概率增强采样（OPES）和驱动绝热自由能动力学（d-AFED），以在统一协议中解决这些采样挑战。对于刚性有机溶质，首先使用带质量缩放的哈密顿量副本交换来量化辛醇溶剂弛豫的影响：将所有辛醇原子质量缩小10倍，在保留平衡溶剂化自由能的同时，使收敛速度提升5倍以上。这些计算为λ-OPES提供了参考基准，λ-OPES是一种双偏置λ-动力学策略，结合了OPES的“标准”和“探索”变体以促进炼金术坐标上的跃迁，该方法在与副本交换相当的时间尺度上达到收敛，且无需预定义的λ窗口或多个并行模拟。对于柔性N-乙酰氨基酸酰胺溶质，λ-OPES与选定主链及侧链二面角上的d-AFED耦合，以实现炼金术与构象增强采样的同步进行。该组合策略提升了与实验辛醇-水分配系数的一致性，将λ-OPES单独使用时的平均绝对误差从0.75对数单位降至λ-OPES-d-AFED组合的0.30对数单位。总体而言，本研究建立了适用于刚性有机溶质和柔性类肽溶质的溶剂化自由能计算的集成增强采样协议，为炼金术自由能方法应用于更大、构象更复杂的系统奠定了基础。
英文摘要：
Accurate solvation free energies from molecular dynamics simulations require efficient sampling of coupled slow variables, including solvent coordinates, solute conformational modes, and the alchemical coordinate $λ$. Here, we develop a $λ$-dynamics framework that combines mass scaling, on-the-fly probability enhanced sampling (OPES), and driven adiabatic free energy dynamics (d-AFED) to address these sampling challenges within a unified protocol. For rigid organic solutes, Hamiltonian replica exchange with mass scaling is first used to quantify the effect of octanol solvent relaxation. Reducing all octanol atomic masses by a factor of ten accelerates convergence by more than fivefold while preserving equilibrium solvation free energies. These calculations then provide reference benchmarks for $λ$-OPES, a dual-bias $λ$-dynamics strategy that combines the "standard" and "explore" variants of OPES to promote transitions along the alchemical coordinate. This approach reaches convergence on timescales comparable to replica exchange, but without predefined $λ$ windows or multiple parallel simulations. For flexible $N$-acetyl amino-acid amide solutes, $λ$-OPES is coupled with d-AFED on selected backbone and side-chain dihedrals to enable simultaneous alchemical and conformational enhanced sampling. This combined strategy improves agreement with experimental octanol-water partition coefficients and reduces the mean absolute error from 0.75 log units with $λ$-OPES alone to 0.30 log units with $λ$-OPES-d-AFED. Overall, this work establishes an integrated enhanced sampling protocol for solvation free energy calculations across rigid organic solutes and flexible peptide-like solutes, and provides a foundation for the application of alchemical free energy methods to larger and more conformationally complex systems.
