A New Paradigm for Biomolecular Simulations

描述（由申请人提供）：该申请涉及广泛的挑战领域（06）使能技术和特定的挑战主题，06- gm -103：开发分子结构，识别和配体相互作用的预测方法。生物医学计算已成为了解生物特性和功能的有力工具。计算生物学的目标是对生化过程进行化学精度的定量预测，即绝对量在1千卡/摩尔以内，相对量在1千卡/摩尔以内。考虑到细胞环境中生物分子系统的复杂性和规模，这是一项艰巨的任务，我们离实现这一重要目标还很遥远。分子计算的核心是描述系统中分子间相互作用的势能函数，通常是势能表面的准确性决定了模拟结果的可靠性。由于近四十年来在参数化方面的巨大努力，目前的分子力学力场在生物分子建模方面取得了很大的成功，但自20世纪60年代末以来，其功能形式几乎没有改变。在这个项目中，我们建议开发一个基于电子结构的量子力学力场，称为显极化（X-Pol）势，用于获得含有蛋白质的生物分子系统的势能表面。这代表了一个重大的范式变化，超越了当前的经典模型，进入了生物医学计算的量子力学领域。X-Pol势是基于可以用半经验或从头算分子轨道理论或密度泛函理论开发的近似层次。证明了这种显式量子力学力场的可行性。这项研究为提高生物医学模拟的计算精度提供了一个巨大的飞跃，并且在这项工作中开发的计算工具将对蛋白质工程和抑制剂设计具有普遍的重要性。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-GM-103: Development of predictive methods for molecular structure, recognition, and ligand interaction. Biomedical computation has become a powerful tool for understanding biological properties and function. The goal of computational biology is to make quantitative predictions of biochemical processes with chemical accuracy, i.e., to within one kcal/mol for absolute quantities and 1 kcal/mol for relative quantities. This is a daunting task in view of the complexity and size of biomolecular systems in a cellular environment, and we are still far from achieving this important goal. At the heart of molecular calculation is the potential energy function that describes intermolecular interactions in the system, and often it is the accuracy of the potential energy surface that determines the reliability of the simulation results. Although the current molecular mechanics force fields have been very successful in biomolecular modeling thanks to tremendous efforts in parameterization in the past forty years, the functional forms have hardly changed since the late 1960s. In this project, we propose to develop an electronic structure-based quantum mechanical force field, called the explicit polarization (X-Pol) potential, for obtaining the potential energy surfaces of biomolecular systems containing proteins. This represents a major paradigm change, going beyond the current classical models to the quantum mechanical realm of biomedical computing. The X-Pol potential is based on a hierarchy of approximations that can be developed using semiempirical or ab initio molecular orbital theory or density functional theory. The feasibility of such an explicit quantum mechanical force field has been demonstrated. The proposed research offers a great opportunity for a quantum leap in improving computational accuracy in biomedical simulation, and the computational tools developed in this work will be of general importance to protein engineering and inhibitor design. PUBLIC HEALT RELEVANCE: Biomedical computation has become a powerful tool for understanding biological properties and function. The research described in this proposal aims at the development of a novel computational approach that represents a paradigm change in the way that we describe intermolecular interactions and it is expected to significantly increase the accuracy of computational results. This in turn can help design inhibitors and engineer specialized proteins for biomedical and industrial applications.