Polarizable Force Field for Proteins and Lipids

家长奖的项目摘要 基于原子模型的分子动力学（MD）模拟在分子动力学研究中发挥着越来越重要的作用。 理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 不可极化的加性FF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。目前正在努力开发和优化一个 用于脂质的可极化FF将允许对广泛的相关过程进行基础模拟研究。 生物膜。在上一个资助期内，我们在开发方面取得了重大进展， 基于经典的Drude振子模型的可极化FF。Drude FF已经在 CHARMM、NAMD、ChemShell QM/MM、GROMACS和OpenMM GPU套件， 微秒时间尺度上的模拟以及利用一系列增强采样的模拟 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，有一个关键的需要，以扩大类型的磷脂所涵盖的德鲁德 FF使更广泛的生物膜系统的建模，超过三分之一的所有MD 生物系统的模拟涉及双层膜。生物膜的极化模型是 有必要解释其复杂的分子性质，其中各种强静电因素 在微观尺度上相互竞争。该计划是执行全局优化， 使用结构、动力学和机械信息作为物理目标，验证脂质的Drude FF 膜数据的优化，并通过晶格和改善非键相互作用的处理 长程货车德瓦耳斯色散（LJ-PME），同时将Drude FF扩展到包括带电的 特别注意离子与极性头基的强相互作用（目标1）。然后我们将 使用改进的Drude FF研究生物膜静电的基本方面，并阐明 电子极化对生物膜基本静电特性的贡献（目的 2)通过对经典的膜电位概念和膜结合电压敏感性的研究， 具有基态和激发态的可极化模型的染料。最后，我们将开发精确的极化 磷脂酰肌醇-4，5-二磷酸（PIP 2）的模型，特别注意与 单价和二价阳离子，以研究离子诱导的域形成和PIP 2的横向聚集（目的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).