Validating polarizability models in macromolecular force fields: The Stark effect

描述（由申请人提供）：极化力场代表了生物大分子（包括蛋白质）理论研究的最新方法。在本研究中，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，直接测试基于经典德鲁德振荡器的极化力场的准确性。适当地描述静电和处理大分子力场中的分子极化性对于发展能够准确描述蛋白质中化学功能之间相互作用的计算方法至关重要。新的极化力场包括极化项，这些极化项通常是从气相小模型系统的量子力学计算中推导出来的。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缩放的极化率值。这种比例因子可以通过再现代表性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，在设计大分子力场时，它包含不同的标度因子，对应于不同的功能，并假设组合模型能够对大分子的电子环境进行全面正确的描述。迄今为止，许多极化力场已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，也没有优化用于蛋白质模拟的极化率缩放参数。我们将通过直接计算探针分子在蛋白质环境中的振动斯塔克效应来解决这些问题。斯塔克效应是一种测量选择功能的振动变化的方法，作为化学环境的函数，信息可能与功能周围的电场直接相关。因此，这一信息可用于直接测试电场在这些官能团周围重现电场的能力。

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.