用生成模型直接计算溶剂自由能，省去繁琐中间步骤
Estimating Solvation Free Energies with Boltzmann Generators
- 基于归一化流模型，直接映射不同大小溶质间的溶剂构型
- 对难处理的溶质膨胀或分离过程，误差可接受且效率更高
- 适合需要快速估算溶剂自由能的分子模拟研究者
准确计算溶剂自由能仍是分子模拟的核心挑战，通常需大量采样和众多代数中间态以确保气相与溶液中溶质相空间分布的充分重叠。本文提出一种基于归一化流的计算框架，直接在不同尺寸溶质间映射溶剂构型，并与传统自由能估算方法进行对比。针对Lennard-Jones溶剂，结果表明该方法在处理溶质生长或溶质间距增大的困难变换时，仍能获得可接受的自由能差估算精度，且无需沿变换路径设置多个中间步骤。径向分布函数分析显示，该流模型生成的溶剂重构具有物理意义，显著提升了构型空间中各状态间的构型重叠度。这些结果表明，基于流的模型是传统自由能估算方法的有前景替代方案。
原文摘要 · Abstract (English)
Accurate calculations of solvation free energies remain a central challenge in molecular simulations, often requiring extensive sampling and numerous alchemical intermediates to ensure sufficient overlap between phase-space distributions of a solute in the gas phase and in solution. Here, we introduce a computational framework based on normalizing flows that directly maps solvent configurations between solutes of different sizes, and compare the accuracy and efficiency to conventional free energy estimates. For a Lennard-Jones solvent, we demonstrate that this approach yields acceptable accuracy in estimating free energy differences for challenging transformations, such as solute growth or increased solute-solute separation, which typically demand multiple intermediate simulation steps along the transformation. Analysis of radial distribution functions indicates that the flow generates physically meaningful solvent rearrangements, substantially enhancing configurational overlap between states in configuration space. These results suggest flow-based models as a promising alternative to traditional free energy estimation methods.
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