Solid State and Structural Chemistry Unit, Indian Institute of Science , C. V. Raman Avenue, Bangalore 560012, India.
J Phys Chem B. 2013 Dec 12;117(49):15625-38. doi: 10.1021/jp406255z. Epub 2013 Nov 7.
We carry out a series of long atomistic molecular dynamics simulations to study the unfolding of a small protein, chicken villin headpiece (HP-36), in water-ethanol (EtOH) binary mixture. The prime objective of this work is to explore the sensitivity of protein unfolding dynamics toward increasing concentration of the cosolvent and unravel essential features of intermediates formed in search of a dynamical pathway toward unfolding. In water-ethanol binary mixtures, HP-36 is found to unfold partially, under ambient conditions, that otherwise requires temperature as high as ∼600 K to denature in pure aqueous solvent. However, an interesting course of pathway is observed to be followed in the process, guided by the formation of unique intermediates. The first step of unfolding is essentially the separation of the cluster formed by three hydrophobic (phenylalanine) residues, namely, Phe-7, Phe-11, and Phe-18, which constitute the hydrophobic core, thereby initiating melting of helix-2 of the protein. The initial steps are similar to temperature-induced unfolding as well as chemical unfolding using DMSO as cosolvent. Subsequent unfolding steps follow a unique path. As water-ethanol shows composition-dependent anomalies, so do the details of unfolding dynamics. With an increase in cosolvent concentration, different partially unfolded intermediates are found to be formed. This is reflected in a remarkable nonmonotonic composition dependence of several order parameters, including fraction of native contacts and protein-solvent interaction energy. The emergence of such partially unfolded states can be attributed to the preferential solvation of the hydrophobic residues by the ethyl groups of ethanol. We further quantify the local dynamics of unfolding by using a Marcus-type theory.
我们进行了一系列长原子分子动力学模拟，以研究在水-乙醇（EtOH）二元混合物中一种小蛋白——鸡绒毛球蛋白头部片段（HP-36）的展开。这项工作的主要目的是研究蛋白质展开动力学对共溶剂浓度增加的敏感性，并揭示形成的中间体的基本特征，以寻找展开的动力学途径。在水-乙醇二元混合物中，HP-36 在环境条件下部分展开，而在纯水溶液中则需要高达约 600 K 的温度才能变性。然而，在这个过程中观察到一个有趣的途径，由形成独特的中间体来指导。展开的第一步基本上是分离由三个疏水性（苯丙氨酸）残基组成的簇，即 Phe-7、Phe-11 和 Phe-18，它们构成了疏水性核心，从而启动了蛋白质的螺旋-2 的融化。初始步骤与温度诱导的展开以及使用 DMSO 作为共溶剂的化学展开相似。随后的展开步骤遵循独特的路径。由于水-乙醇表现出组成依赖性异常，因此展开动力学的细节也是如此。随着共溶剂浓度的增加，发现形成了不同的部分展开中间体。这反映在几个序参数的显著非单调组成依赖性上，包括天然接触分数和蛋白质-溶剂相互作用能。这种部分展开状态的出现可以归因于乙醇的乙基基团对疏水性残基的优先溶剂化。我们进一步通过马库斯型理论来量化展开的局部动力学。
