Esque Jeremy, Cecchini Marco
Laboratoire d'Ingénierie des Fonctions Moléculaires (ISIS), UMR 7006 CNRS, Université de Strasbourg, F-67083 Strasbourg Cedex, France.
J Phys Chem B. 2015 Apr 23;119(16):5194-207. doi: 10.1021/acs.jpcb.5b01632. Epub 2015 Apr 9.
The calculation of the free energy of conformation is key to understanding the function of biomolecules and has attracted significant interest in recent years. Here, we present an improvement of the confinement method that was designed for use in the context of explicit solvent MD simulations. The development involves an additional step in which the solvation free energy of the harmonically restrained conformers is accurately determined by multistage free energy perturbation simulations. As a test-case application, the newly introduced confinement/solvation free energy (CSF) approach was used to compute differences in free energy between conformers of the alanine dipeptide in explicit water. The results are in excellent agreement with reference calculations based on both converged molecular dynamics and umbrella sampling. To illustrate the general applicability of the method, conformational equilibria of met-enkephalin (5 aa) and deca-alanine (10 aa) in solution were also analyzed. In both cases, smoothly converged free-energy results were obtained in agreement with equilibrium sampling or literature calculations. These results demonstrate that the CSF method may provide conformational free-energy differences of biomolecules with small statistical errors (below 0.5 kcal/mol) and at a moderate computational cost even with a full representation of the solvent.
构象自由能的计算是理解生物分子功能的关键，近年来引起了广泛关注。在此，我们对用于显式溶剂分子动力学模拟的约束方法进行了改进。改进过程涉及一个额外步骤，即通过多级自由能微扰模拟准确确定谐波约束构象的溶剂化自由能。作为一个测试案例应用，新引入的约束/溶剂化自由能（CSF）方法用于计算丙氨酸二肽在显式水中不同构象之间的自由能差异。结果与基于收敛分子动力学和伞形抽样的参考计算结果高度吻合。为了说明该方法的普遍适用性，还分析了甲硫氨酸脑啡肽（5个氨基酸）和十肽丙氨酸（10个氨基酸）在溶液中的构象平衡。在这两种情况下，都获得了与平衡抽样或文献计算结果一致的平滑收敛的自由能结果。这些结果表明，CSF方法可以以适度的计算成本提供生物分子构象自由能差异，且统计误差较小（低于0.5千卡/摩尔），即使在完全考虑溶剂的情况下也是如此。
