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）：可极化力场代表了生物大分子（包括蛋白质）理论研究的最先进方法。在拟议的研究中，我们将通过计算旨在绘制蛋白质电场图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。对静电的正确描述和对大分子力场中分子极化性的处理对于计算方法的发展至关重要，该方法可以准确地描述蛋白质中化学功能之间的相互作用。新的极化力场包括通常从气相小模型系统的量子力学计算中得出的极化项。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，因此必须对选定类别的官能团使用按比例缩放的极化率值。这些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系统。因此，当设计大分子力场时，它包含对应于不同功能的不同比例因子，并假设组合模型能够产生对大分子电子环境的整体正确描述。迄今为止，许多极化力场已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，或优化蛋白质模拟中使用的极化率缩放参数。我们将通过直接计算蛋白质环境中探针分子的振动斯塔克效应来解决这些问题。斯塔克效应是对选定功能的振动变化的测量，作为化学环境的函数，这些信息可能与功能周围的电场直接相关。因此，该信息可以用作力场再现这些功能组周围电场的能力的直接测试。 公共健康相关性：这些计算中的信息将验证应用于蛋白质的极化率缩放的假设，并作为力场进一步优化的基础，以更准确地表示蛋白质中的电场。由此产生的改进的极化力场将为蛋白质的计算研究提供新工具，包括药物发现和优化，从而有助于蛋白质抑制剂的设计，包括新型治疗剂。