CORE RESEARCH GRANT

核心研究补助金

• 批准号: 8171941
• 负责人: CHARLES L BROOKS
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171941
• 关键词: Address; Biological; Biological Models; Biology; Charge; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Development; Electronics; Ensure; Enzymes; Funding; Generations; Goals; Grant; Hydrogen; Institution; Investigation; Ions; Learning; Mechanics; Modeling; Molecular; Nucleic Acids; Performance; Proteins; Research; Research Personnel; Research Project Grants; Resources; Role; Source; Statistical Mechanics; System; Techniques; Testing; United States National Institutes of Health; Vacuum; base; models and simulation; quantum; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this continuing Core Project is the development and testing of a new force field for interaction models of biological molecules which includes the effects of electronic charge polarization. We have explored different means for incorporating electronic polarizability into classical empirical force fields for biological molecules. We have settled on our current direction that encompasses the use of a class of polarizable models based on the quantum mechanical principal of charge equalization, and which utilizes the ideas of fluctuating charge distributions via extended systems techniques from statistical mechanics. These approaches have been fully implemented into the CHARMM1 molecular simulation and modeling package during the current grant period and will continue to be optimized for performance and functionality with other modules within CHARMM during the coming grant period. The primary task to be addressed during the pending grant period is the development of a consistent parameterization of the polarizable force field that is useful for modeling both protein and nucleic acid systems, and is compatible with the current generation CHARMM all hydrogen force fields (the version 22 and 28 force fields). To accomplish these goals, we have assembled the necessary quantum chemical tools, e.g., GAMESS/COSMO2,3 and GAMESS4, for the characterization of the "polarized" and vacuum charge distributions needed in developing polarizability parameters for protein and nucleic acid building blocks. We will use these tools to develop the needed model system parameterizations. Furthermore, we have developed a collaborative relationship with Alex MacKerell, the primary developer of the current generation CHARMM force fields, to ensure that the resulting polarizable force field will be parameterized in a manner consistent with existing force fields that do not include the effects of electronic charge polarization. Our main focus during the pending grant period will be to complete the first generation parameterization of a force field for biomolecular systems and perform testing to begin exploration of the role of electronic charge polarization in modulating interactions in proteins and nucleic acids. We are now poised to complete this parameter development, leading to the first generation of polarizable force fields for biological molecules. We note that this is not anticipated to provide force fields that are (initially) more accurate than existing mean field polarizable force fields (present generation empirical force fields). Instead, we aim to provide the basis for understanding when and where polarizable force fields are important in biology, and to learn how better to treat these situations. We are enthusiastic about the opportunities that such a class of force fields will open up to us. For example, we can anticipate that a deeper understanding of ion selectivity in enzymes and nucleic acid systems will be amenable to first principles investigation with this type of force field.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这个持续核心项目的目标是开发和测试 用于生物分子相互作用模型的新力场，其中包括 电子电荷极化的影响。 我们探索了结合电子极化性的不同方法 进入生物分子的经典经验力场。 我们有 确定了我们当前的方向，其中包括使用一类 基于电荷量子力学原理的极化模型 均衡，利用了波动电荷分布的思想 通过统计力学的扩展系统技术。 这些方法 已完全实施到 CHARMM1 分子模拟和建模中 当前资助期内的软件包，并将继续优化 CHARMM 中其他模块的性能和功能 即将到来的资助期。 等待拨款期间要解决的首要任务是 极化力场一致参数化的发展 这对于模拟蛋白质和核酸系统很有用，并且是 与当前一代 CHARMM 所有氢力场兼容（ 版本 22 和 28 力场）。 为了实现这些目标，我们聚集了 必要的量子化学工具，例如 GAMESS/COSMO2,3 和 GAMESS4， 所需的“极化”和真空电荷分布的表征 开发蛋白质和核酸构建的极化参数 块。 我们将使用这些工具来开发所需的模型系统 参数化。 此外，我们还建立了合作关系 与当代 CHARMM 的主要开发人员 Alex MacKerell 合作 力场，以确保产生的极化力场将是 以与现有力场一致的方式参数化，但不 包括电子电荷极化的影响。 期间我们的主要关注点 等待拨款期将是完成第一代 生物分子系统力场的参数化并进行测试 开始探索电子电荷极化的作用 调节蛋白质和核酸的相互作用。 我们现在准备完成此参数开发，从而实现第一个 产生生物分子的极化力场。 我们注意到 预计这不会提供（最初）更大的力场 比现有的平均场极化力场（当代 经验力场）。 相反，我们的目标是提供基础 了解极化力场在生物学中何时何地很重要， 并学习如何更好地处理这些情况。 我们热衷于 此类力场将为我们带来机遇。 为了 例如，我们可以预期对离子选择性的更深入了解 酶和核酸系统将服从第一原理 用这种类型的力场进行调查。