Chemistry Department, University of Florence, Via Lastruccia n.3, I-50019 Sesto Firentino, Italy.
Molecules. 2022 Jul 11;27(14):4426. doi: 10.3390/molecules27144426.
In the context of computational drug design, we examine the effectiveness of the enhanced sampling techniques in state-of-the-art free energy calculations based on alchemical molecular dynamics simulations. In a paradigmatic molecule with competition between conformationally restrained E and Z isomers whose probability ratio is strongly affected by the coupling with the environment, we compare the so-called λ-hopping technique to the Hamiltonian replica exchange methods assessing their convergence behavior as a function of the enhanced sampling protocols (number of replicas, scaling factors, simulation times). We found that the pure λ-hopping, commonly used in solvation and binding free energy calculations via alchemical free energy perturbation techniques, is ineffective in enhancing the sampling of the isomeric states, exhibiting a pathological dependence on the initial conditions. Correct sampling can be restored in λ-hopping simulation by the addition of a "hot-zone" scaling factor to the λ-stratification (FEP approach), provided that the additive hot-zone scaling factors are tuned and optimized using preliminary ordinary replica-exchange simulation of the end-states.
在计算药物设计的背景下，我们研究了增强采样技术在基于化学动力学模拟的最新自由能计算中的有效性。在一个典范的分子中，构象受限的 E 和 Z 异构体之间存在竞争，其概率比受与环境的耦合强烈影响，我们比较了所谓的 λ-跃迁技术和哈密顿复制交换方法，评估了它们作为增强采样方案（副本数量、缩放因子、模拟时间）的函数的收敛行为。我们发现，在通过化学自由能扰动技术进行溶剂化和结合自由能计算中常用的纯 λ-跃迁技术，在增强异构态采样方面效果不佳，表现出对初始条件的病态依赖性。通过向 λ-分层（FEP 方法）添加“热点”缩放因子，可以在 λ-跃迁模拟中恢复正确的采样，前提是使用最终状态的常规副本交换模拟来调整和优化附加的热点缩放因子。
