Lai Thanh T, Brooks Charles L
Biophysics Program, University of Michigan, Ann Arbor, Michigan 48103, United States.
Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, Michigan 48103, United States.
J Chem Theory Comput. 2025 Sep 9;21(17):8320-8329. doi: 10.1021/acs.jctc.5c00807. Epub 2025 Aug 20.
Umbrella sampling (US) is a cornerstone enhanced sampling technique that constructs potentials of mean force (PMF) by biasing a system of interest along a set of collective variables (CV). With a good choice of CVs, one can uncover the free energy landscapes governing a plethora of biological processes such as protein-ligand (un)binding, protein (un)folding, and enzyme catalysis. However, multiple sets of umbrella simulations have to be run when one is interested in exploring how the free energy landscape of a particular process varies with chemical space, such as the effects of different mutations on the (un)folding landscape or how different ligands (un)bind to the same protein. We propose an enhanced sampling framework called MSλD + US that couples umbrella sampling with multisite λ dynamics (MSλD) to leverage MSλD's hallmark feature of sampling multiple chemical species in one simulation. In doing so, we recast the characterization of free energy landscapes for multiple chemical species into a simultaneous search of conformational and chemical landscapes. We validate MSλD + US's ability to construct multiple PMFs from a single set of umbrella simulations using three test systems of increasing complexity, with the most complex system involving the (un)binding PMFs of two ligands from trypsin.
伞形采样（US）是一种重要的增强采样技术，它通过沿着一组集体变量（CV）对感兴趣的系统施加偏置来构建平均力势（PMF）。通过合理选择CV，人们可以揭示控制众多生物过程的自由能景观，如蛋白质-配体（非）结合、蛋白质（非）折叠和酶催化。然而，当人们想要探究特定过程的自由能景观如何随化学空间变化时，例如不同突变对（非）折叠景观的影响或不同配体如何（非）结合到同一蛋白质上，就需要运行多组伞形模拟。我们提出了一种名为MSλD + US的增强采样框架，它将伞形采样与多位点λ动力学（MSλD）相结合，以利用MSλD在一次模拟中对多种化学物种进行采样的标志性特征。通过这样做，我们将对多种化学物种的自由能景观的表征重新构建为对构象景观和化学景观的同时搜索。我们使用三个复杂度不断增加的测试系统验证了MSλD + US从单组伞形模拟构建多个PMF的能力，其中最复杂的系统涉及两种配体与胰蛋白酶的（非）结合PMF。
