在小分子隐式溶剂模拟中处理熵和构象变化。
Treating entropy and conformational changes in implicit solvent simulations of small molecules.
作者信息
Mobley David L, Dill Ken A, Chodera John D
机构信息
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA.
出版信息
J Phys Chem B. 2008 Jan 24;112(3):938-46. doi: 10.1021/jp0764384. Epub 2008 Jan 3.
Abstract
Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TDeltaS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid.
摘要
隐式溶剂模型在分子模拟和其他应用中用于估算水合（水化）自由能越来越受欢迎。在许多情况下，这些模型的参数是为了重现小分子水合自由能的实验值而推导出来的。通常，这些水合自由能是针对单个溶质构象计算的，忽略了溶质在水合时的构象变化。在这里，我们使用炼金术自由能方法纳入这些效应。我们发现，即使对于相对较小、简单、刚性的溶质，仅使用单个溶质构象估算水合自由能时也会出现显著误差。例如，我们发现水合时构象熵（TDeltaS）变化高达2.3千卡/摩尔。有趣的是，这些构象熵的变化与可旋转键的数量相关性很差（R2 = 0.03）。本研究表明，通过消除溶质是刚性的近似，可以改进隐式溶剂建模。
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