Polarizable Force Field for Proteins and Lipids

描述（由申请人提供）：基于原子模型的计算在理解生物分子系统中发挥着越来越重要的作用。到目前为止，这些计算通常是使用潜在的功能，占多体极化效应的平均方式，使用有效的参数化的原子部分电荷。为了克服第一个资助期内的这一限制，我们着手开发蛋白质和脂质的势能函数，其中包括通过经典德鲁德振荡器模型显式处理诱导电子极化。在本补助金提交的研究重点是完成的参数优化目标模型化合物的代表蛋白质和脂质，然后通过测试的大分子系统中的开发力场存在广泛的实验数据。目标1中基于小分子的优化将靶向代表pKa计算所需的氨基酸电离状态的化合物，并使用二-和多肽量子力学和实验数据优化phi、psi主链和chi侧链参数。在目标1中开发的参数将在一系列具有不同螺旋，β折叠和β转角倾向的模型多肽上进行测试，通过在明确的溶剂中的Hamiltonian回火复制交换，并在溶液和晶体环境中模拟高分辨率蛋白质，以验证力场可以重现实验上可访问的结构和动态特性。目标3将集中在定量评价的力场再现能量可观的能力，包括在选定的蛋白质，氧化还原电位和电子转移率rubredoxin，合作的钙结合蛋白D9 K的EF-手的钙结合蛋白，和脂质单层和双层的界面电位pKa位移。在完成拟议的研究后，一个最先进的蛋白质和脂质的可极化经验力场将提供给计算化学界。此外，将获得关于电子极化对一些生物现象的贡献的新见解。 公共卫生相关性：本研究项目的目标是完成一个明确解释蛋白质和膜的诱导极化的力场的发展。这样的力场将具有改进的精度，这将允许对具有生物医学重要性的广泛分子系统进行逼真的计算机模拟。这些类型的计算机模拟也在药物发现和铅优化中发挥着至关重要的作用。

DESCRIPTION (provided by applicant): Computations based on atomistic models are playing an increasingly important role in understanding biomolecular systems. To date, these computations have typically been performed using potential functions that account for many-body polarization effects in an average way using an effective parameterization of the atomic partial charges. To overcome this limitation during the first funding period we have undertaken the development of a potential energy function for proteins and lipids that includes the explicit treatment of induced electronic polarization via the classical Drude oscillator model. The studies proposed in the present grant submission focus on completion of the optimization of parameters targeting model compounds representative of proteins and lipids followed by testing of the developed force field in macromolecular systems for which extensive experimental data exist. Small molecule based optimization in Aim 1 will target compounds representing ionization states of amino acids required for pKa calculations and optimization of the phi, psi backbone and chi sidechain parameters using di- and polypeptide quantum mechanical and experimental data. Parameters developed in Aim 1 will be tested on a series of model polypeptides with different helical, beta sheet and beta turn propensities via Hamiltonian tempering replica-exchange in explicit solvent and in simulations of high-resolution proteins both in solution and crystal environments to validate that the force field can reproduce experimentally accessible structural and dynamic properties. Aim 3 will focus on quantitative evaluation of the ability of the force field to reproduce energetic observables including pKa shifts in selected proteins, redox potentials and electron transfer rates in rubredoxin, cooperative binding of Ca2+ to the EF-hands in calbindin D9k, and interfacial potentials of lipid monolayers and bilayers. Upon completion of the proposed study a state-of-the-art polarizable empirical force field for proteins and lipids will be available to the computational chemistry community. In addition, novel insights on the contribution of electronic polarization to a number of biological phenomena will be obtained. PUBLIC HEALTH RELEVANCE: The goal of this research project is to complete the development of a force field accounting explicitly for induced polarization for proteins and membranes. Such a force field will have an improved accuracy that will permit realistic computer simulations of a wide range of molecular systems that have biomedical importance. These types of computer simulations also play a critical role in the drug discovery and lead optimization.