Validating polarizability models in macromolecular force fields: The Stark effect

验证大分子力场中的极化率模型：斯塔克效应

• 批准号: 7803433
• 负责人: Ashley Lauren Ringer
• 金额: $ 4.56万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2012-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803433
• 关键词: Accounting; Address; Agreement; Amino Acids; Area; Arts; Benchmarking; Biological; Biological Models; Chemicals; Complement; Complex; Computing Methodologies; Data; Development; Electronics; Electrostatics; Environment; Equilibrium; Evaluation; Fellowship; Frequencies; Gases; Goals; Maps; Measures; Mechanics; Methodology; Methods; Modeling; Molecular; Peptides; Phase; Property; Proteins; Quantum Mechanics; Reproduction; Sampling; Solvents; Structure; System; Testing; Theoretical Studies; Thermodynamics; Training; Vertebral column; Work; base; chemical function; computer studies; design; drug discovery; electric field; electronic structure; functional group; improved; macromolecule; molecular dynamics; molecular mechanics; novel; public health relevance; quantum; research study; simulation; small molecule; tool; vibration

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.

描述（由申请人提供）：可极化力场代表了包括蛋白质在内的生物大分子的理论研究的最先进方法。在拟议的研究中，我们将通过计算基于经典的Drude振荡器来直接测试可极化力场的准确性，该探针分子的振动Stark效应旨在绘制旨在绘制蛋白质电场的探针分子。对大分子力场中静电和分子极化率的治疗的正确描述对于可以准确描述蛋白质化学功能之间的相互作用的计算方法的发展至关重要。新的可极化力场包括在气相中小型模型系统上经常得出的极化项。但是，在许多情况下，气相极化性不适用于凝结相模拟，因此必须将缩放的极化值用于选定的官能团类别。然后将这种缩放因子直接应用于大分子系统。因此，当设计大分子力场时，它包含与不同功能相对应的不同缩放因子，并且合并模型假定对大分子的电子环境产生了整体正确的描述。迄今为止，已经应用了许多可极化的力场，以用于蛋白质的分子模拟。但是，这些研究都没有直接验证了力场的静电模型，或优化了蛋白质模拟中使用的极化缩放参数。我们将通过直接计算蛋白质环境中探针分子的振动鲜明效应来解决这些问题。鲜明的效果是衡量所选功能作为化学环境函数振动的变化，这可能与功能周围的电场直接相关的信息。因此，该信息可以用作对力场在这些功能组周围重现电场的能力的直接测试。 公共卫生相关性：这些计算中的信息将验证应用于蛋白质的极化缩放的假设，并充当对力场进行额外优化的基础，以更准确地代表蛋白质中的电场。所得改善的两极分化力场将为包括药物发现和优化在内的蛋白质计算研究提供新的工具，从而有助于蛋白质不耐受剂的设计，包括新型的theraupentic剂。