Theoretical Studies of Aqueous Solvation of Proteins

生物大分子的水溶剂化理论的发展对于理解其结构和功能至关重要。本研究将发展大分子溶剂化理论，并将其应用于模拟算法中，研究水和反离子与蛋白质的特定相互作用。简单的连续介质溶剂模型不足以描述诸如氢键、局部介电扰动和仅涉及少数水层分离的现象。为了理解和模拟溶剂化的分子性质，这里使用的方法是发展统计力学积分方程理论。首先，先前提出的球形分子溶剂化的积分方程理论将扩展到蛋白质。为了促进这一点，将开发一种新的水模拟模型，该模型在结构性质上相当于TIP4P，但比蒙特卡罗模拟中的3点水模型快三倍。无需进一步发展，这一理论就可以用来预测给定结构的溶剂化；例如，蛋白质的晶体或核磁共振结构。其次，大分子的水溶剂化理论将被纳入动力学模拟算法。目前，在分子动力学模拟中加入显式溶剂是唯一一种包括水的分子性质的模拟方法，但它在计算机资源上非常昂贵。讨论了几种不同的结合这一理论的方法。最终目标是将离子强度效应纳入模拟方法。生物大分子的水溶剂化理论的发展对于理解它们的结构和功能至关重要。这项研究将发展大分子溶剂化和计算的理论，然后可以用于研究水和反离子与蛋白质的特定相互作用。这个理论可以用来预测给定结构的溶剂化；例如，蛋白质的晶体或核磁共振结构。其次，大分子的水溶剂化理论将被纳入动力学模拟算法。最终目标是将离子强度效应纳入模拟方法。＊＊＊

9506796 Ichiye The development of theories of aqueous solvation of biological macromolecules is crucial to understanding their structure and function. This research will develop theories for macromolecular solvation and implement them into simulation algorithms and to study specific interactions of water and counterions with proteins. Simple continuum solvent models are insufficient to describe phenomena such as hydrogen bonding, local dielectric perturbations and phenomena involving separations of only a few water layers. To understand and model the molecular nature of solvation, the approach used here is the development of statistical mechanical integral equation theories. First, the previously proposed integral equation theory for solvation of globular molecules will be extended to proteins. To facilitate this, a new model of water for simulations will be developed, which is equivalent to TIP4P in structural properties but is three times faster than 3-site water models in Monte Carlo simulations. Without further development, this theory can then be used to predict the solvation of a given structure; e.g., a crystal or NMR structure of a protein. Second, this theory of aqueous solvation of macromolecules will be incorporated into dynamics simulation algorithms. Currently, addition of explicit solvent into a molecular dynamics simulation is the only simulation method to include the molecular nature of water, but it is very costly in computer resources. Several different methods of incorporating this theory are discussed. The final goal is incorporation of ionic strength effects into simulation methods. %%% The development of theories of aqueous solvation of biological macromolecules is crucial to understanding their structure and function. This research will develop theories for macromolecular solvation and calculations that can then be used to study specific interactions of water and counterions with proteins. This theory can be used to predict t he solvation of a given structure; e.g., a crystal or NMR structure of a protein. Second, this theory of aqueous solvation of macromolecules will be incorporated into dynamics simulation algorithms. The final goal is incorporation of ionic strength effects into simulation methods. ***