Eichenberger Andreas P, van Gunsteren Wilfred F, Riniker Sereina, von Ziegler Lukas, Hansen Niels
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland.
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH, CH-8093 Zürich, Switzerland.
Biochim Biophys Acta. 2015 May;1850(5):983-995. doi: 10.1016/j.bbagen.2014.09.014. Epub 2014 Sep 18.
The contribution of particular hydrogen bonds to the stability of a protein fold can be investigated experimentally as well as computationally by the construction of protein mutants which lack particular hydrogen-bond donors or acceptors with a subsequent determination of their structural stability. However, the comparison of experimental data with computational results is not straightforward. One of the difficulties is related to the representation of the unfolded state conformation.
A series of molecular dynamics simulations of the 34-residue WW domain of protein Pin1 and 20 amide-to-ester mutants started from the X-ray crystal structure and the NMR solution structure are analysed in terms of backbone-backbone hydrogen bonding and differences in free enthalpies of folding in order to provide a structural interpretation of the experimental data available.
The contribution of the different β-sheet hydrogen bonds to the relative stability of the mutants with respect to wild type cannot be directly inferred from experimental thermal denaturation temperatures or free enthalpies of chaotrope denaturation for the different mutants, because some β-sheet hydrogen bonds show sizeable variation in occurrence between the different mutants.
A proper representation of unfolded state conformations appears to be essential for an adequate description of relative stabilities of protein mutants.
The simulations may be used to link the structural Boltzmann ensembles to relative free enthalpies of folding between mutants and wild-type protein and show that unfolded conformations have to be treated with a sufficient level of detail in free energy calculations of protein stability. This article is part of a Special Issue entitled Recent developments of molecular dynamics.
特定氢键对蛋白质折叠稳定性的贡献可以通过实验和计算来研究，即构建缺乏特定氢键供体或受体的蛋白质突变体，随后测定其结构稳定性。然而，将实验数据与计算结果进行比较并非易事。其中一个困难与未折叠状态构象的表示有关。
从X射线晶体结构和核磁共振溶液结构出发，对蛋白质Pin1的34个残基的WW结构域和20个酰胺-酯突变体进行了一系列分子动力学模拟，分析了主链-主链氢键以及折叠自由焓的差异，以便对现有实验数据进行结构解释。
不同β-折叠氢键对突变体相对于野生型的相对稳定性的贡献不能直接从不同突变体的实验热变性温度或离液剂变性自由焓中推断出来，因为一些β-折叠氢键在不同突变体之间的出现频率有相当大的变化。
未折叠状态构象的恰当表示对于充分描述蛋白质突变体的相对稳定性似乎至关重要。
这些模拟可用于将结构玻尔兹曼系综与突变体和野生型蛋白质之间的折叠相对自由焓联系起来，并表明在蛋白质稳定性的自由能计算中，必须以足够详细的程度处理未折叠构象。本文是名为“分子动力学的最新进展”的特刊的一部分。
