DEVELOPMENT OF A NEXT-GENERATION NUCLEIC ACID FORCE FIELD

描述（由申请人提供）：生物分子建模和模拟是理解分子生物学和结构生物化学的物理启发方法的核心。在过去的几年里，经验力场已经接近一个世代的过渡，从建立良好、调整良好但本质上有限的固定点电荷模型转向更复杂和准确的极化电位。本研究提出将可极化的AMOEBA （Atomic Multipole Optimized Energetics for biommolecular Applications）力场扩展到核酸系统。结合目前的阿米巴蛋白参数化，这将为两种主要的生物聚合物类别提供一致的衍生模型。核酸所需的静电参数将由高级量子力学电子结构计算得出。为了将阿米巴用于DNA和RNA系统，需要几种新的能量功能来处理目前被忽视的效应，如电荷转移、电子密度渗透和短距离范围内色散的阻尼。由此产生的下一代阿米巴力场有望显著提高其他现有力场的短程相互作用精度。核酸及其与离子、小分子和蛋白质的相互作用是人类生物化学、生理学和遗传学的基础。本研究将校正阿米巴原虫核酸在一系列结构基序上的电位，针对药物rna结合数据，以及与离子的相互作用。经过验证的力场将为转录因子与DNA相互作用的建模、氨基糖苷类抗生素与核糖体的详细结合计算以及目前用极化力场无法解决的类似问题开辟未来的机会。

DESCRIPTION (provided by applicant): Biomolecular modeling and simulation lies at the heart of physically inspired methods for understanding molecular biology and structural biochemistry. Empirical force fields have been approaching a generational transition over the past several years, moving away from well- established, well-tuned but intrinsically limited fixed point charge models towards more intricate and accurate polarizable potentials. This research proposes to extend the polarizable AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field to nucleic acid systems. Together with the current AMOEBA protein parameterization, this will provide a consistently derived model for the two major biopolymer classes. The required electrostatic parameter for nucleic acids will be derived from high-level quantum mechanical electronic structure calculations. In order to use AMOEBA for DNA and RNA systems, several new energy functions will be needed to treat currently neglected effects, such as charge transfer, penetration of electron densities, and damping of dispersion at short distance ranges. The resulting next-generation of the AMOEBA force field promises to significantly improve the accuracy of short-range interactions over other currently available force fields. Nucleic acids, and their interaction with ions, small molecules and proteins, underlie much of human biochemistry, physiology and genetics. This research will calibrate the AMOEBA nucleic acid potentials on a series of structural motifs, against drug-RNA binding data, and with respect to interactions with ions. The validated force field will then open future opportunities for modeling of transcription factor interactions with DNA, detailed binding calculations for aminoglycoside antibiotics with the ribosome, and similar problems not approachable at present with polarizable force fields.