Abstract Free energy calculations are central to understanding the structure, dynamics and function of biomolecules. Yet insufficient sampling of biomolecular configurations is often regarded as one of the main sources of error. Many enhanced sampling techniques have been developed to address this issue. Notably, enhanced sampling methods based on biasing collective variables (CVs), including the widely used umbrella sampling, adaptive biasing force and metadynamics, have been discussed in a recent excellent review (Abrams and Bussi, Entropy, 2014). Here, we aim to review enhanced sampling methods that do not require predefined system-dependent CVs for biomolecular simulations and as such do not suffer from the hidden energy barrier problem as encountered in the CV-biasing methods. These methods include, but are not limited to, replica exchange/parallel tempering, self-guided molecular/Langevin dynamics, essential energy space random walk and accelerated molecular dynamics. While it is overwhelming to describe all details of each method, we provide a summary of the methods along with the applications and offer our perspectives. We conclude with challenges and prospects of the unconstrained enhanced sampling methods for accurate biomolecular free energy calculations.

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用于生物分子自由能计算的无约束增强采样：综述

摘要 自由能计算是理解生物分子结构、动力学和功能的核心。然而，生物分子构型的采样不足通常被视为误差的主要来源之一。已经开发了许多增强的采样技术来解决这个问题。值得注意的是，基于偏置集体变量 (CV) 的增强抽样方法，包括广泛使用的伞状抽样、自适应偏置力和元动力学，已在最近的一篇优秀评论中进行了讨论（Abrams 和 Bussi，Entropy，2014）。在这里，我们的目标是审查增强的采样方法，这些方法不需要用于生物分子模拟的预定义系统相关 CV，因此不会遇到 CV 偏置方法中遇到的隐藏能量障碍问题。这些方法包括但不限于，副本交换/平行回火、自导分子/朗之万动力学、基本能量空间随机游走和加速分子动力学。虽然描述每种方法的所有细节很困难，但我们提供了方法的摘要以及应用程序，并提供了我们的观点。我们总结了用于精确生物分子自由能计算的无约束增强采样方法的挑战和前景。