Implicit modeling of nonpolar solvation for simulating protein folding and conformational transitions
Implicit modeling of nonpolar solvation for simulating protein folding and conformational transitions
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DOI：
10.1039/b714141f
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发表时间：
2008-01-01
影响因子：
3.3
通讯作者：
Brooks, Charles L., III
中科院分区：
文献类型：
--
作者：
Chen, Jianhan;Brooks, Charles L., III
在蛋白质结构和动力学的计算机模拟中，对溶剂环境的准确描述至关重要。溶剂的隐式处理旨在通过直接估算溶剂化自由能来捕捉水分子对溶质的平均影响。它已成为显式溶剂的一种有力替代方法，并在计算成本和细节水平之间提供了一种良好的折衷。我们回顾了在模拟蛋白质折叠和构象转变的背景下非极性溶剂化隐式建模的当前理论和技术，并讨论了进一步发展的主要方向。研究表明，当前基于表面积的非极性模型存在严重局限性，包括对溶剂化的构象依赖性描述不足、对成对非极性相互作用强度的高估以及对三体疏水相互作用的反协同性的错误预测。我们认为，要在隐式溶剂模型的当前精度水平上有所提高，需要纳入非极性溶剂化的两个重要方面，即疏水相互作用的长度尺度依赖性以及溶质 - 溶质色散相互作用的溶剂屏蔽。我们认识到在构建一个足够平衡且合理高效的隐式溶剂蛋白质力场方面存在巨大挑战。尽管如此，大多数基本问题已被理解，并且在过去几年中已经取得了令人兴奋的进展。我们相信，沿着所概述的前沿领域持续开展工作将极大地提高人们在原子细节水平上研究蛋白质折叠和大构象转变的能力。
Accurate description of the solvent environment is critical in computer simulations of protein structure and dynamics. An implicit treatment of solvent aims to capture the mean influence of water molecules on the solute via direct estimation of the solvation free energy. It has emerged as a powerful alternative to explicit solvent, and provides a favorable compromise between computational cost and level of detail. We review the current theory and techniques for implicit modeling of nonpolar solvation in the context of simulating protein folding and conformational transitions, and discuss the main directions for further development. It is demonstrated that the current surface area based nonpolar models have severe limitations, including insufficient description of the conformational dependence of solvation, over-estimation of the strength of pair-wise nonpolar interactions, and incorrect prediction of anti-cooperativity for three-body hydrophobic associations. We argue that, to improve beyond current level of accuracy of implicit solvent models, two important aspects of nonpolar solvation need to be incorporated, namely, the length-scale dependence of hydrophobic association and solvent screening of solute - solute dispersion interactions. We recognize that substantial challenges exist in constructing a sufficiently balanced, yet reasonably efficient, implicit solvent protein force field. Nonetheless, most of the fundamental problems are understood, and exciting progress has been made over the last few years. We believe that continual work along the frontiers outlined will greatly improve one's ability to study protein folding and large conformational transitions at atomistic detail.