Institute of Thermodynamics and Thermal Process Engineering , University of Stuttgart , D-70569 Stuttgart , Germany.
J Chem Inf Model. 2018 Nov 26;58(11):2305-2318. doi: 10.1021/acs.jcim.8b00581. Epub 2018 Nov 5.
Relative folding free energies for a series of amide-to-ester mutations in the Pin1-WW domain are calculated using molecular dynamics simulations. Special focus is given to the identification and elimination of a simulation-related bias which was observed in previous work (Eichenberger et al. Biochim. Biophys. Acta 2015, 1850, 983) by comparing simulation results obtained with two different starting structures. Subtle local variations in the protein starting structure may lead to substantial deviations in the calculated free-energy changes as a consequence of differences in the sampled ϕ/ψ-dihedral angle distributions of the mutated residue. It is found that the combination of alchemical transformation with Hamiltonian replica exchange for enhanced sampling reduces the starting structure dependence considerably. Compared to previous work, the improved sampling of both the folded and unfolded states also improves the agreement between simulation and experiment.
采用分子动力学模拟计算了 Pin1-WW 结构域中一系列酰胺到酯突变的相对折叠自由能。特别关注了在之前的工作（Eichenberger 等人，生物化学。生物物理。 Acta 2015, 1850, 983）中观察到的与模拟相关的偏差的识别和消除，通过比较两种不同起始结构获得的模拟结果。蛋白质起始结构中的细微局部变化可能会导致计算出的自由能变化出现很大偏差，这是由于突变残基的采样ϕ/ψ 二面角分布的差异所致。研究发现，通过阿尔加尔变换与哈密顿副本交换相结合进行增强采样，可以大大降低起始结构的依赖性。与之前的工作相比，折叠态和展开态的改进采样也提高了模拟与实验之间的一致性。
