Polarizable Force Field for Proteins and Lipids

蛋白质和脂质的极化力场

• 批准号: 10798692
• 负责人: BENOIT ROUX
• 金额: $ 4.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798692
• 关键词: Attention; Award; Binding; Biological; Biological Models; Carbohydrates; Charge; Complex; Data; Development; Divalent Cations; Electronics; Electrostatics; Funding; Ions; Lateral; Length; Lipids; Mechanics; Membrane; Microscopic; Modeling; Molecular; Monovalent Cations; Nature; Nucleic Acids; Parents; Phosphatidylinositol 4,5-Diphosphate; Phospholipids; Play; Process; Property; Proteins; Role; Sampling; Structure; Sum; System; Technology; Time; Validation; Water; biological systems; driving force; improved; molecular dynamics; simulation; voltage sensitive dye; zeta potential

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).

家长奖项目摘要 基于原子模型的分子动力学（MD）模拟在以下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，精确且经验的力场 (FF) 是必要的。虽然 不可极化的附加 FF 是有用的近似值，生物膜的极化模型是 需要解释它们复杂的分子性质。目前正在努力开发和优化 用于脂质的可极化 FF 将允许对各种相关过程进行基础模拟研究 与生物膜。在上一个资助期间，我们在开发方面取得了重大进展 基于经典 Drude 振荡器模型的可极化 FF。 Drude FF 已实施于 CHARMM、NAMD、ChemShell QM/MM、GROMACS 和 OpenMM GPU 套件，允许公正 微秒时间尺度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。此时迫切需要扩大 Drude 所涵盖的磷脂类型 FF 能够对更广泛的生物膜系统进行建模，超过三分之一的 MD 生物系统的模拟涉及双层膜。生物膜的极化模型是 有必要考虑其复杂的分子性质，其中存在各种强静电因素 在微观长度尺度上相互竞争。该计划是执行全局优化和 使用结构、动力学和机械信息作为物理目标验证 Drude FF 的脂质 用于优化的膜数据，并通过晶格和改进非键相互作用的处理 远程范德瓦尔斯色散 (LJ-PME)，同时扩展德鲁德 FF 以覆盖带电 脂质，特别关注离子与极性头基的强相互作用（目标 1）。我们随后将 使用改进的 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（目标 2）研究了经典的 z 电位概念和膜结合电压敏感特性 具有基态和激发态偏振模型的染料。最后，我们将开发精确的偏光 磷脂酰肌醇-4,5-二磷酸 (PIP2) 模型，特别注意与 单价和二价阳离子来研究离子诱导的 PIP2 结构域形成和横向聚类（目标 3）。

项目成果

Many-body polarization effects and the membrane dipole potential.

• DOI: 10.1021/ja806825g
• 发表时间: 2009-03-04
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Harder E;Mackerell AD Jr;Roux B
• 通讯作者: Roux B

Representation of Ion-Protein Interactions Using the Drude Polarizable Force-Field.

• DOI: 10.1021/jp510560k
• 发表时间: 2015-07-23
• 期刊: The journal of physical chemistry. B
• 作者: Li H;Ngo V;Da Silva MC;Salahub DR;Callahan K;Roux B;Noskov SY
• 通讯作者: Noskov SY

Integrated Continuum Dielectric Approaches to treat Molecular Polarizability and the Condensed Phase: Refractive Index and Implicit Solvation.

处理分子极化性和凝聚相的集成连续介电方法：折射率和隐式溶剂化。

• DOI: 10.1021/ct900029d
• 发表时间: 2009
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Truchon,Jean-François;Nicholls,Anthony;Roux,Benoît;Iftimie,RaduI;Bayly,ChristopherI
• 通讯作者: Bayly,ChristopherI

Correction to intrinsic energy landscapes of amino acid side-chains.

修正氨基酸侧链的内在能量景观。

• DOI: 10.1021/ci300301x
• 发表时间: 2012
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Zhu,Xiao;Lopes,PedroEM;Shim,Jihyun;MackerellJr,AlexanderD
• 通讯作者: MackerellJr,AlexanderD

Accurate Molecular Polarizabilities Based on Continuum Electrostatics.

基于连续静电学的精确分子极化率。

• DOI: 10.1021/ct800123c
• 发表时间: 2008
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Truchon,Jean-Francois;Nicholls,Anthony;Iftimie,RaduI;Roux,Benoit;Bayly,ChristopherI
• 通讯作者: Bayly,ChristopherI