Theoretical Studies of Aqueous Solvation of Proteins

这个项目将有助于更好地理解蛋白质-水相互作用的物理起源，以及液态水的异常性质。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，其性质仍未被完全了解。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)利用计算机模拟了解蛋白质溶剂化的本质。本项目的重点是开发新的软粘偶极-四极-八极（SSDQO）水势能模型，用于生物系统的计算机模拟。SSDQO模型是对旧的软粘偶极子（SSD）单点模型的改进，由于它具有更好的结构、介电和动力学特性，并且在分子动力学（MD）模拟中快4倍，在蒙特卡罗（MC）模拟中快7倍，因此是生物模拟中常用的三点模型的进步。新的SSDQO模型是一个单点模型，具有一个Lennard-Jones球和一个点偶极子、四极子和八极子，新的粘性相互作用势是一个近似的矩膨胀。第一个目标是优化SSDQO模型的力矩参数，以再现液态水的性质。热力学、动力学和结构性能将使用MD和/或MC模拟计算，并与实验数据进行比较。一旦对非极化模型进行优化，就会加入与CHARMM力场一致的极化。第二个目标是阐明蛋白质-水相互作用的基本物理原理。首先，将通过MD和/或MC模拟研究简单肽在SSDQO水中的溶剂化，并与实验数据进行比较。接下来，我们将利用MD模拟研究SSDQO水在溶液和结晶环境下的红霉素，并与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起源，这对于验证该模型在各种条件下的使用也很重要，例如在拥挤的活细胞中。在MD模拟中，将SSDQO势的能量分解为矩项，研究SSDQO水的密度和扩散常数对温度的依赖关系。第四个目标是将SSDQO模型扩展到蛋白质等复杂分子，这是本研究的一个未来方向。将近似矩扩展扩展到其他分子和化学部分（如分子内的肽）的可行性将通过MC模拟进行检验。该项目将提高计算机模拟各种涉及液态水的生物、化学和物理系统的速度和准确性。该模型将与CHARMM力场兼容，并将在CHARMM计算机程序中实现，CHARMM计算机程序广泛用于生物分子的分子力学/动力学研究。因此，该模型将很容易被其他研究人员使用。这项研究还将训练学生在计算科学方面的能力。首席研究员的小组在民族和种族上是多元化的，目前有两名女研究生。外联工作将侧重于妇女，她们在数学和计算科学领域的代表性传统上不足。

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.