CORE RESEARCH GRANT

核心研究补助金

• 批准号: 8364378
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364378
• 关键词: Address; Biological; Biological Models; Biology; Biomedical Research; Charge; Chemicals; Development; Electronics; Ensure; Enzymes; Funding; Generations; Goals; Grant; High Performance Computing; Hydrogen; Investigation; Ions; Learning; Mechanics; Modeling; Molecular; National Center for Research Resources; Nucleic Acids; Performance; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Source; Statistical Mechanics; System; Techniques; Testing; United States National Institutes of Health; Vacuum; base; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这个持续的核心项目的目标是开发和测试 生物分子相互作用模型的新力场，包括 电子电荷极化的影响。 我们已经探索了不同的方法来纳入电子极化率 生物分子的经典经验力场。 我们有 我们确定了当前的方向，包括使用一类 基于量子力学电荷原理的极化模型 均衡，并利用波动电荷分布的想法 通过统计力学的扩展系统技术。 这些方法 已完全实施到CHARMM 1分子模拟和建模中 包在当前的赠款期间，并将继续优化， 性能和功能与CHARMM内的其他模块， 即将到来的赠款期。 在等待赠款期间要处理的主要任务是 可极化力场一致参数化的发展 其可用于蛋白质和核酸系统的建模，并且 与当前一代CHARMM兼容的所有氢力场（ 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/COSMO 2、3和GAMESS 4，用于 所需的“极化”和真空电荷分布的表征 在开发用于蛋白质和核酸构建的极化率参数时， 个街区. 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， Alex Mackerell，当前一代CHARMM的主要开发人员 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进行参数化， 包括电子电荷极化的影响。 我们的主要重点在 即将到来的拨款期将完成第一代 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在 调节蛋白质和核酸的相互作用。 我们现在准备完成这个参数的开发，从而实现第一个 为生物分子产生可极化的力场。 我们注意到 这并不预期提供（最初）更大的力场， 比现有的平均场极化力场（当代）精确 经验力场）。 相反，我们的目标是提供基础， 了解何时何地可极化力场在生物学中很重要， 并学习如何更好地对待这些情况。 我们热衷于 这类力场将为我们提供的机会。 为 例如，我们可以预见，更深入地了解离子选择性， 酶和核酸系统将服从第一原理 用这种力场进行调查