Polarizable Force Field for Proteins and Lipids

来自家长奖的项目总结 基于原子模型的分子动力学(MD)模拟在许多领域发挥着越来越重要的作用 了解驱动生物膜结构和动力学的基本物理力。 然而，为了进行有意义的模拟，准确和经验的力场(FF)是必要的。虽然 不可极化的添加剂F是有用的近似，生物膜的可极化模型是 需要解释它们复杂的分子性质。目前开发和优化 可极化的脂类FF将允许对相关过程的广泛范围进行基础模拟研究 使用生物膜。在上一次融资期间，我们在开发方面取得了重大进展 基于经典的德鲁德振子模型的可极化FF。Drude FF已在 CHARMM、NAMD、ChemShell QM/MM、GROMACS和OpenMM GPU套件，允许无偏见 微秒时间尺度上的模拟以及利用增强采样范围的模拟 技术。我们已经可以模拟水、离子、蛋白质、核酸、碳水化合物和一些中性物质 磷脂。在这一点上，迫切需要扩大DRUD覆盖的磷脂类型 使更广泛的生物膜系统的建模成为可能，因为超过三分之一的MD 生物系统的模拟涉及双层膜。生物膜的极化模型有 有必要说明其复杂的分子性质，其中存在各种强烈的静电因素 在微观的长度尺度上相互竞争。该计划是执行全局优化和 以结构、动力学和机械信息为物理目标验证Drude FF的血脂有效性 用于优化膜数据，并通过晶格和改进非键合相互作用的处理 长程范德华色散(LJ-PME)，同时将Drude FF扩展到覆盖带电 脂类，特别注意离子与极性头基的强相互作用(目标1)。到时候我们会的 使用精制的Drude FF研究生物膜静电学的基本方面，并阐明 电子极化对生物膜基本静电特性的贡献(AIM 2)研究了经典的ζ电势概念和膜结合压敏材料的特性 具有基态和激发态可极化模型的染料。最后，我们将开发精确的偏振器 磷脂酰肌醇-4，5-二磷酸(PIP2)的模型，特别注意与 一价阳离子和二价阳离子研究PIP2的离子诱导结构域形成和侧向聚集(目标3)。

PROJECT SUMMARY from the Parent Award Molecular dynamics (MD) simulations based on atomistic models play an increasingly important role in understanding the fundamental physical forces driving the structure and dynamics of biological membranes. However, to have meaningful simulations, accurate and empirical force fields (FFs) are necessary. Although nonpolarizable additive FFs are useful approximations, polarizable models of biological membranes are needed to account for their complex molecular nature. The present efforts to develop and optimize a polarizable FF for lipids will allow fundamental simulation studies of a broad range of processes associated with biological membranes. During the last funding period we made significant progress with the development of a polarizable FF based on the classical Drude oscillator model. The Drude FF has been implemented in CHARMM, NAMD, ChemShell QM/MM, GROMACS and the OpenMM GPU suite, allowing for unbiased simulations on the microsecond time scale as well as simulations exploiting a range of enhanced sampling technologies. We can already model water, ions, proteins, nucleic acids, carbohydrates, and a few neutral phospholipids. At this point there is a critical need to expand the type of phospholipids covered by the Drude FF to enable the modeling of a wider range of biological membrane systems, as over one third of all MD simulations of biological systems involve bilayer membranes. Polarizable models of biological membranes are necessary to account for their complex molecular nature, where a variety of strong electrostatic factors compete with one another over microscopic length-scales. The plan is to perform a global optimization and validation of the Drude FF for lipids using structural, dynamical, and mechanical information as physical target membrane data for the optimization, and improve the treatment of nonbonded interactions via a lattice sum of the long-range van der Waals dispersion (LJ-PME), and simultaneously extend the Drude FF to cover charged lipids with a special attention to the strong interactions of ions with the polar headgroup (Aim 1). We will then use the refined Drude FF to study fundamental aspects biomembrane electrostatics and elucidate the contribution of electronic polarization on the fundamental electrostatics features of biological membranes (Aim 2) with a study of the classical concept of ζ-potential and the properties of membrane-bound voltage-sensitive dyes with polarizable models for the ground and excited state. Lastly, we will develop accurate polarizable models of phosphatidylinositol-4,5-bisphosphate (PIP2), with a special attention to the interactions with monovalent and divalent cations to study ion-induced domain formation and lateral clustering of PIP2 (Aim 3).