Polarizable Force Field for Proteins and Lipids

蛋白质和脂质的极化力场

• 批准号: 8965099
• 负责人: ALEXANDER D MACKERELL
• 金额: $ 39.78万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965099
• 关键词: Accounting; Acetylcholine; Agreement; Allosteric Regulation; Area; Binding; Binding Proteins; Biological Phenomena; Biological Process; Cells; Charge; Chemicals; Cholesterol; Collection; Communities; Complex; Computer Simulation; Cytochrome c Peroxidase; Data; Dependence; Development; Electronics; Electrostatics; Engineering; Funding; Generations; Goals; Hydrocarbons; Hydrogen Bonding; Investigation; Ions; Ligand Binding; Ligands; Lipids; Measurement; Measures; Mechanics; Medical; Membrane; Membrane Proteins; Metals; Methodology; Modeling; Molecular; Osmotic Pressure; Peptides; Pharmaceutical Preparations; Play; Potential Energy; Production; Property; Protein Dynamics; Proteins; Reproduction; Research Project Grants; Role; Sampling; Solutions; Spectrum Analysis; Sphingomyelins; Structure; System; Temperature; Theoretical Studies; Thrombin; Time; Work; aqueous; base; chromophore; computational chemistry; density; driving force; drug development; drug discovery; functional group; improved; insight; large scale simulation; method development; novel; peptide structure; physical model; protein complex; protein structure; public health relevance; quantum; simulation; solid state nuclear magnetic resonance; solute; voltage

 DESCRIPTION (provided by applicant): Computations based on atomistic models play an increasingly important role in understanding biomolecular systems as well as in drug development. Improvements in these models involve extensions of the underlying functional form of the potential energy as well as additional optimization targeting a wider range of experimental and quantum mechanical data. During the last funding period we made significant advances in the development of empirical force fields (FF) for proteins and lipids, with improvements to the CHARMM additive models and the production of polarizable models for proteins, lipids and ions based on the classical Drude oscillator model. The Drude FF has already been implemented in CHARMM, NAMD, ChemShell QM/MM and the OpenMM GPU suite, and is currently usable for MD simulations on the order of one microsecond as well as with Temperature and Hamiltonian Replica-Exchange sampling methodologies. In the proposed study we will investigate how the explicit treatment of electronic polarization contributes to the structure, dynamics and biological functions of proteins, lipids and ligand binding. In Aim 1 we will apply the polarizable FF to investigate the physical forces driving the folding and conformational properties of peptides and proteins as well as evaluate and further optimize the protein model targeting a range of properties. These will include quantum mechanical data, NMR observables, pKa shifts and aqueous solution data on ionic and polar neutral species representative of biomolecules, including osmotic pressure and density experimental data measured as part of this study. Membrane and protein-membrane complexes will be studied in Aim 2 using the polarizable FF with emphasis on the permeation of small species, translocation of cell penetrating peptides, and interpretation of experimental data from solution and solid state NMR, scattering, voltage-sensitive membrane-bound chromophores and 2D-IR spectroscopy. Information from these calculations will allow for additional optimization of the lipid FF and its extension to unsaturated and anionic lipids, cholesterol and sphingomyelin. Aim 3 will investigate protein-ligand interactions including the forces driving the binding of ions and drug-like molecules. The impact of electronic polarization on these interactions will be investigated with the goal of achieving a more accurate representation of ligand binding. The energy function will be extended to account for charge transfer in the case of ion binding if it is deemed necessary. Additional efforts will include development of an automated parameter optimization utility for drug-like molecules. Upon completion of the proposed study we will have an improved understanding of the physical forces driving protein and membrane structure and dynamics based on a highly optimized state-of-the-art polarizable empirical FF that will be available to the computational chemistry community, including the capability to apply the polarizable model in drug discovery.

 描述（应用程序提供）：基于原子模型的计算在理解生物分子系统以及药物开发中起着越来越重要的作用。这些模型的改进涉及势能的潜在功能形式的扩展以及针对更广泛的实验和量子机械数据的其他优化。在最后的资金期间，我们在蛋白质和脂质的经验力场（FF）开发方面取得了重大进步，并改善了CHARMM其他模型，并基于经典的振动振荡器模型的蛋白质，脂质和离子的极化模型的产生。 DRUDE FF已经在Charmm，NAMD，Chemshell QM/MM和OpenMM GPU套件中实施，目前可用于MD模拟，以一微秒和温度和汉密尔顿复制品复制方法的订单。在拟议的研究中，我们将研究电子极化的显式处理如何促进蛋白质，脂质和配体结合的结构，动力学和生物学功能。在AIM 1中，我们将应用可极化的FF来研究驱动胡椒粉和蛋白质的折叠和构象性能的物理力，并评估并进一步优化针对一系列特性的蛋白质模型。这些将包括量子机械数据，NMR可观察物，PKA移位以及代表生物分子的离子和极性中性物种的水溶液数据，包括作为本研究的一部分测量的渗透压和密度实验数据。膜和蛋白质 - 膜复合物将在AIM 2中使用可极化的FF进行研究，重点是小种物种的渗透，易位的细胞穿透辣椒的易位，以及解释溶液和固态的实验数据 NMR，散射，电压敏感的膜结合的发色团和2D-IR光谱。这些计算中的信息将允许脂质FF及其扩展到不饱和和阴离子脂质，胆固醇和鞘磷脂的扩展。 AIM 3将研究蛋白质 - 配体相互作用，包括驱动离子和药物样分子结合的力。电子极化对这些相互作用的影响将进行研究，目的是实现更准确的配体结合。如果有必要，则将扩展能量函数以考虑离子结合的情况。额外的努力将包括开发用于药物样分子的自动参数优化实用程序。拟议的研究完成后，我们将根据高度优化的最优化的极化经验FF对驱动蛋白质和膜结构和动态的物理力的理解有了改进的了解 计算化学界，包括在药物发现中应用可极化模型的能力。