CORE RESEARCH GRANT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该持续核心项目的目标是开发和测试 一种用于生物分子相互作用模型的新的力场，包括 电子电荷极化的影响。 我们已经探索了结合电子极化率的不同方法 生物分子的经典经验力场。我们有 确定了我们当前的方向，包括使用一类 基于电荷量子力学原理的极化模型 均衡化，并利用波动电荷分布的思想 通过来自统计力学的扩展系统技术。这些方法 已经完全实现到CHARMM1分子模拟和建模中 包在当前的授权期内，并将继续针对 CHARMM内其他模块的性能和功能 即将到来的授权期。 在未决的授权期内要解决的主要任务是 极化力场的一致参数化法的发展 这对蛋白质和核酸系统的建模都很有用，而且是 兼容当前一代的CHARMM所有氢力场( 版本22和28力场)。为了实现这些目标，我们聚集在一起 必要的量子化学工具，如GAMESS/COSMO2，3和GAMESS4，用于 所需的“极化”和真空电荷分布的表征 在开发蛋白质和核酸构建的极化率参数中 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，我们还发展了一种协作关系 与当代CHARMM的主要开发者Alex MacKerell 力场，以确保产生的可极化力场将是 以与现有力场一致的方式参数化，这些力场不 包括电子电荷极化的影响。我们的主要工作重点是 悬而未决的授权期将是完成第一代 生物分子系统力场的参数化及测试 开始探索电子电荷极化在…中的作用 调节蛋白质和核酸之间的相互作用。 我们现在准备完成这个参数开发，导致第一个 生物分子极化力场的产生。我们注意到 预计这不会提供(最初)更多的力场 比现有的平均场可极化力场(当代)更精确 经验力场)。相反，我们的目标是为 了解可极化力场在生物学中何时何地是重要的， 并学习如何更好地处理这些情况。我们热衷于 这样一类力场将向我们敞开的机会。为 例如，我们可以预期，对离子选择性的更深入理解 酶和核酸系统将服从第一原理。 使用这种力场进行调查。

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.