Goette Maik, Grubmüller Helmut
Theoretical and Computational Biophysics Department, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
J Comput Chem. 2009 Feb;30(3):447-56. doi: 10.1002/jcc.21073.
The molecular-dynamics-based calculation of accurate free energy differences for biomolecular systems is a challenging task. Accordingly, convergence and accuracy of established equilibrium methods has been subject of many studies, often focusing at small test systems. In contrast, the potential of more recently proposed nonequilibrium methods, derived from the Jarzynski and Crooks equalities, has not yet fully been explored. Here, we compare the performance of these methods by calculating free energy differences for test systems at different levels of complexity and varying extent of the involved perturbations. We consider the interconversion of ethane into methanol, the switching of a tryptophane-sidechain in a tripeptide, and the binding of two different ligands to the globular protein snurportin 1. On the basis of our results, we suggest and assess a new nonequilibrium free energy method, Crooks Gaussian Intersection (CGI), which combines the advantages of existing methods. CGI is highly parallelizable and, for the test systems considered here, is shown to outperform the other studied equilibrium and nonequilibrium methods.
基于分子动力学计算生物分子系统精确的自由能差是一项具有挑战性的任务。因此，已确立的平衡方法的收敛性和准确性一直是许多研究的主题，这些研究通常聚焦于小型测试系统。相比之下，最近从雅尔津斯基等式和克鲁克斯等式推导出来的非平衡方法的潜力尚未得到充分探索。在这里，我们通过计算不同复杂程度和不同扰动程度的测试系统的自由能差来比较这些方法的性能。我们考虑了乙烷向甲醇的相互转化、三肽中色氨酸侧链的转换以及两种不同配体与球状蛋白核转运蛋白1的结合。基于我们的结果，我们提出并评估了一种新的非平衡自由能方法——克鲁克斯高斯交点法（CGI），它结合了现有方法的优点。CGI具有高度可并行性，并且对于这里考虑的测试系统，它的表现优于其他研究的平衡和非平衡方法。
