Theoretical Studies of Aqueous Solvation of Proteins

该项目将有助于更好地理解蛋白质-水相互作用的物理起源以及液态水的反常性质。水在蛋白质的结构和功能中起着至关重要的作用，如折叠、酶活性和分子识别。然而，水是一种复杂的溶剂，其性质仍未完全了解。该项目的总体目标是：1)在生物大分子的计算机模拟中开发快速和准确的溶剂效应处理方法；2)通过计算机模拟了解蛋白质溶剂化的本质。该项目的重点是开发新的软，粘性偶极-四极-八极(SSDQO)水的势能模型，用于生物系统的计算机模拟。SSDQO模型是对旧的软、粘性偶极(SSD)单点模型的改进，它比通常用于生物模拟的三点模型有更好的结构、介电和动力学性质，但在分子动力学(MD)和蒙特卡罗(MC)模拟中速度分别快4倍和7倍。新的SSDQO模型是一个含有Lennard-Jones球和点偶极、四极和八极的单点模型，新的粘性相互作用势是近似的力矩展开。第一个目标是优化SSDQO模型的矩参数，以再现液态水的性质。热力学、动力学和结构性质将使用MD和/或MC模拟进行计算，并与实验数据进行比较。一旦非极化模型被优化，极化将被添加到与CHARMM力场一致的位置。第二个目标是阐明蛋白质-水相互作用的基本物理学。首先，我们将通过分子动力学和/或分子动力学模拟研究简单多肽在SSDQO水中的溶剂化过程，并与实验数据进行比较。接下来，我们将使用分子动力学模拟来研究溶液和晶体环境中使用SSDQO水的Rubredoxin，并与使用TIP3P水和高分辨率晶体结构的模拟进行比较。第三个目标是确定液态水异常性质的物理来源，这对于验证模型在广泛条件下的使用也很重要，例如在拥挤的活细胞中。在分子动力学模拟中，将能量分解为SSDQO势中的力矩项，研究SSDQO水的密度和扩散常数与温度的关系。第四个目标是将SSDQO模型扩展到蛋白质等复杂分子，这代表了这一研究的未来方向。将通过MC模拟来检验将近似矩展开扩展到其他分子和分子内的多肽等化学部分的可行性。该项目将提高对涉及液态水的各种生物、化学和物理系统的计算机模拟的速度和准确性。该模型将与CHARMM力场兼容，并将被实现到CHARMM计算机程序中，该程序广泛用于生物分子的分子力学/动力学研究。因此，其他研究人员可以很容易地访问该模型。这项研究还将培训学生学习计算科学。首席调查员的群体是族裔和种族多元化的，目前有两名女性研究生。外联工作将侧重于妇女，她们在科学的数学和计算领域传统上代表性不足。

This project will lead to a better understanding of the physical origins of protein-water interactions and also the anomalous properties of liquid water. Water plays a crucial role in the structure and function of proteins such as in folding, enzymatic activity, and molecular recognition. However, water is a complex solvent whose properties are still not completely understood. The overall goals of this project are 1) to develop fast and accurate treatments of solvent effects in computer simulations of biological macromolecules and 2) to understand the nature of protein solvation using computer simulations. The focus of this project is on the development of the new soft, sticky dipole-quadrupole-octopole (SSDQO) potential energy model of water for computer simulations of biological systems. The SSDQO model is a modification of the old soft, sticky dipole (SSD) single-point model, which was an advance over the three-site models commonly used for biological simulations because it has better structural, dielectric and dynamical properties and yet is four times faster in molecular dynamics (MD) and seven times faster in Monte Carlo (MC) simulations. The new SSDQO model is a single-point model with a Lennard-Jones sphere and a point dipole, quadrupole, and octopole and the new sticky interaction potential is an approximate moment expansion. The first objective is to optimize the moment parameters of the SSDQO model to reproduce the properties of liquid water. Thermodynamic, dynamic and structural properties will be calculated using MD and/or MC simulations and compared with experimental data. Once the non-polarizable model is optimized, polarization will be added consistent with the CHARMM force field. Second objective is to elucidate the underlying physics of protein-water interactions. First, the solvation of simple peptides in SSDQO water will be studied by MD and/or MC simulations and compared with experimental data. Next, rubredoxin in solution and crystalline environment using SSDQO water will be studied using MD simulations and compared to simulations using TIP3P water and a high-resolution crystal structure. Third objective is to determine the physical origins of the anomalous properties of liquid water, which is also important for validating the use of the model under a wide range of conditions such as in a crowded living cell. The temperature dependence of the density and of the diffusion constant of SSDQO water will be studied in MD simulations using the decomposition of the energy into moment terms in the SSDQO potential. Fourth objective is to extend the SSDQO model to complicated molecules such as proteins, which represents a future direction for this research. The feasibility of extending the approximate moment expansion to other molecules and chemical moieties such as peptides within molecules will be examined via MC simulations. This project will lead to increased speed and accuracy of computer simulations of a wide variety of biological, chemical and physical systems involving liquid water. The model will be made compatible with the CHARMM force field and will be implemented into the CHARMM computer program, which is widely used for molecular mechanics/dynamics studies of biomolecules. Thus, the model will be readily accessible to other researchers. This research will also train students in computational science. The principal investigator's group is ethnically and racially diverse and currently has two female graduate students. Outreach efforts will focus on women, who are traditionally underrepresented in mathematical and computational areas of science.