Blondel Arnaud
Unité de Repliement et Modélisation des Protéines, and Unité de Bioinformatique Structurale (CNRS URA 2185), Institut Pasteur, F-75724, Paris Cedex 15, France.
J Comput Chem. 2004 May;25(7):985-93. doi: 10.1002/jcc.20025.
Thermodynamic integration is a widely used method to calculate and analyze the effect of a chemical modification on the free energy of a chemical or biochemical process, for example, the impact of an amino acid substitution on protein association. Numerical fluctuations can introduce large uncertainties, limiting the domain of application of the method. The parametric energy function describing the chemical modification in the thermodynamic integration, the "Alchemical path," determines the amplitudes of the fluctuations. In the present work, I propose a measure of the fluctuations in the thermodynamic integration and an approach to search for a parametric energy path minimizing that measure. The optimal path derived with this approach is very close to the theoretical minimum of the measure, but produces nonergodic sampling. Nevertheless, this path is used to guide the design of a practical and efficient path producing correct sampling. The convergence with this practical path is evaluated on test cases, and compares favorably with that of other methods such as power or polynomial path, soft-core van der Waals, and some other approaches presented in the literature.
热力学积分是一种广泛使用的方法，用于计算和分析化学修饰对化学或生化过程自由能的影响，例如氨基酸取代对蛋白质缔合的影响。数值波动会引入很大的不确定性，限制了该方法的应用范围。在热力学积分中描述化学修饰的参数能量函数，即“炼金术路径”，决定了波动的幅度。在本工作中，我提出了一种衡量热力学积分波动的方法，以及一种寻找使该度量最小化的参数能量路径的方法。用这种方法导出的最优路径非常接近该度量的理论最小值，但会产生非遍历采样。尽管如此，该路径仍被用于指导设计产生正确采样的实用且高效的路径。在测试案例上评估了该实用路径的收敛性，并与其他方法（如幂或多项式路径、软核范德华力以及文献中提出的其他一些方法）进行了比较，结果表现良好。
