Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Science, Vienna Muthgasse 18, 1190 Vienna, Austria.
J Chem Theory Comput. 2021 Jan 12;17(1):56-65. doi: 10.1021/acs.jctc.0c01170. Epub 2020 Dec 22.
Thermodynamic integration (TI) is a commonly used method to determine free-energy differences. One of its disadvantages is that many intermediate λ-states need to be sampled in order to be able to integrate accurately over ⟨∂/∂λ⟩. Here, we use the recently introduced extended TI to study alternative parameterizations of (λ) and its influence on the smoothness of the ⟨∂/∂λ⟩ curves as well as the efficiency of the simulations. We find that the extended TI approach can be used to select curves of low curvature. An optimal parameterization is suggested for the calculation of hydration free energies. For calculations of relative binding free energies, we show that optimized parameterizations of the Hamiltonian in the unbound state also effectively lower the curvature in the bound state of the ligand.
热力学积分（TI）是一种常用于确定自由能差的方法。它的一个缺点是，为了能够准确地对 ⟨∂/∂λ⟩ 进行积分，需要对许多中间 λ 态进行采样。在这里，我们使用最近引入的扩展 TI 来研究（λ）的替代参数化及其对 ⟨∂/∂λ⟩ 曲线平滑度以及模拟效率的影响。我们发现，扩展 TI 方法可用于选择曲率较低的曲线。针对水合自由能的计算，我们提出了一种最佳参数化方案。对于相对结合自由能的计算，我们表明，在非结合状态下对哈密顿量进行优化的参数化也可以有效地降低配体结合状态的曲率。
