Validating polarizability models in macromolecular force fields: The Stark effect

描述(申请人提供)：可极化力场代表了包括蛋白质在内的生物大分子理论研究的最先进方法。在这项拟议的研究中，我们将通过计算用于绘制蛋白质电场的探针分子的振动斯塔克效应，直接测试基于经典Drude振子的可极化力场的准确性。在大分子力场中正确描述静电学和处理分子的极化率对于发展能够准确描述蛋白质化学功能之间相互作用的计算方法是至关重要的。新的可极化力场包括经常从气相中的小模型系统的量子力学计算中得到的极化项。然而，在许多情况下，气相极化率已被证明不适用于凝聚相模拟，因此必须对选定的官能团类别使用标度的极化值。这些比例因子可以通过再现典型纯溶剂的介电常数来确定，然后直接应用于大分子体系。因此，当设计一个大分子力场时，它包含对应于不同官能度的不同标度因子，组合模型假定给出了对大分子电子环境的全面正确描述。到目前为止，许多极化力场已经被应用于蛋白质的分子模拟。然而，这些研究都没有直接验证力场的静电模型，也没有优化蛋白质模拟中使用的极化率标度参数。我们将通过直接计算蛋白质环境中探针分子的振动斯塔克效应来解决这些问题。斯塔克效应是对所选功能的振动随化学环境的变化而变化的测量，这些信息可能与功能周围的电场直接相关。因此，该信息可用作力场在这些官能团周围重现电场的能力的直接测试。 与公共健康相关：这些计算的信息将验证应用于蛋白质的极化比例假设，并作为进一步优化力场的基础，以更准确地表示蛋白质中的电场。由此得到的改进的极化力场将为蛋白质的计算研究提供新的工具，包括药物发现和优化，从而有助于蛋白质抑制剂的设计，包括新型热敏剂。

DESCRIPTION (provided by applicant): Polarizable force fields represent the state of the art method for theoretical studies of biological macromolecules, including proteins. In the proposed study, we will directly test the accuracy of a polarizable force field based on the classical Drude oscillator via calculations of the vibrational Stark effect for probe molecules designed to map the electric field of proteins. The proper description of electrostatics and treatment of molecular polarizability in macromolecular force fields is critical to the development of computational methodologies which can accurately describe interactions between chemical functionalities in proteins. New polarizable force fields include polarizability terms frequently derived from quantum mechanical computations on small model systems in the gas phase. However, in a number of cases the gas phase polarizabilities have been shown to not be applicable for condensed phase simulations, such that scaled polarizability values must be used for selected classes of functional groups. Such scaling factors, which may be determined via the reproduction of dielectric constants of representative pure solvents, are then applied directly to macromolecular systems. Thus, when a macromolecular force field is designed, it contains different scaling factors corresponding to different functionalities, with the combined model assumed to yield an overall correct description of the electronic environment of the macromolecule. To date, a number of polarizable force fields have been applied for molecular simulations of proteins. However, none of these studies has directly validated the electrostatic model of the force field, or optimized the polarizability scaling parameters used in protein simulations. We will address these questions by directly computing the vibrational Stark effect for a probe molecule in a protein environment. The Stark effect is a measure of the shift in vibrations of selected functionalities as a function of chemical environment, information that may be directly related to the electric field surrounding the functionality. This information therefore may be used as a direct test of the ability of a force field to reproduce the electric field around those functional groups. PUBLIC HEALTH RELEVANCE: Information from these calculations will validate assumptions on polarizability scaling as applied to proteins and act as the basis for additional optimization of the force field to more accurately represent the electric fields in proteins. The resulting improved polarizable force field will provide new tools for computational studies of proteins, including drug discovery and optimization, thereby aiding in the design of protein inhbitiors, including novel theraupetic agents.