A Kirkwood-Buff Approach to Improved Cosolvent Force Fields

改进共溶剂力场的 Kirkwood-Buff 方法

• 批准号: 0090483
• 负责人: Paul Smith
• 金额: $ 27万
• 依托单位: Kansas State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0090483&HistoricalAwards=false
• 关键词: Kirkwood; Buff; Approach; Improved; Cosolvent

Smith, Paul E.MCB-0090483Cosolvents can have dramatic effects on the properties of peptides and proteins in solution. They are often used to enhance the stability of proteins or to denature them in order to study protein folding. Exactly how cosolvents affect peptides and proteins is unknown. An understanding of these effects will greatly improve our current ideas concerning the nature of the denatured state of proteins. In turn, this will help to clarify the protein folding process by providing a well defined initial state from which one can rationalize the effects of temperature or denaturants. Experimental studies of the denatured states of proteins are limited due to the many conformations available to the protein, and an inability of techniques to determine the interactions between proteins and cosolvent molecules with atomic level resolution. In principle, computer simulations can provide atomic level resolution of denatured proteins and their interactions with cosolvents. However, computer simulation experimentsare only as reliable as the force fields which describe the interactions between the different species. In this proposal, it is shown that current cosolvent force fields need to be improvedin order to quantitatively reproduce the experimental properties of cosolvent mixtures with water. A combination of molecular dynamics simulation and the Kirkwood-Buff theory of mixtures will be used to provide sufficient data for comparison with experiment, and to ensure the quality of the force field. Both effective pair potentials and polarizable models will be investigated for sodium chloride, guanidinium chloride, urea, and 2,2,2 trifluoroethanol; which represent common cosolvents displaying a range of effects on peptides and proteins. The improved force fields will then be used to fully characterize, with atomic detail, the properties of these solutions. This is the first step in determining their different effects on proteins, and is absolutely essential if one is to have any confidence in computer simulation results for these systems.

共溶剂可以对溶液中的多肽和蛋白质的性质产生显著的影响。它们经常被用来增强蛋白质的稳定性，或者为了研究蛋白质折叠而变性蛋白质。辅助剂究竟是如何影响多肽和蛋白质的尚不清楚。对这些影响的理解将极大地改进我们目前关于蛋白质变性状态的性质的想法。反过来，这将有助于澄清蛋白质折叠过程，因为它提供了一个定义良好的初始状态，人们可以从这个状态合理地解释温度或变性剂的影响。对蛋白质变性状态的实验研究是有限的，这是因为蛋白质有许多构象可用，并且无法用原子水平分辨率来确定蛋白质和助溶剂分子之间的相互作用。原则上，计算机模拟可以提供变性蛋白质及其与共溶剂的相互作用的原子水平分辨率。然而，计算机模拟实验只有描述不同物种之间相互作用的力场才是可靠的。在这个方案中，需要改进目前的助溶剂力场，以便定量地再现助溶剂与水的混合物的实验性质。将分子动力学模拟和柯克伍德-布夫混合物理论相结合，为实验提供足够的数据进行比较，并确保力场的质量。氯化钠、氯化胍、尿素和2，2，2-三氟乙醇的有效对电位和极化模型都将被研究，它们代表了对多肽和蛋白质表现出一系列影响的常见助溶剂。改进后的力场将被用来充分表征这些溶液的性质，并提供原子细节。这是确定它们对蛋白质的不同影响的第一步，如果要对这些系统的计算机模拟结果有任何信心，这是绝对必要的。