From Theory of Energy Decomposition Analysis to Rational Force Field Design

Teresa Head-Gordon和Martin Head-Gordon得到了化学部化学理论、模型和计算方法计划颁发的奖项的支持，以开发可用于对复杂分子和双分子系统的行为做出准确预测的计算和理论模型和方法。这个合作项目结合了先进力场的共同开发和能量分解分析(EDA)。目前生物分子建模和模拟领域依赖于分子势能面的简单表示，其基础是众所周知的“成对相加”力场。但为了设计新的药物或新的生物材料，该领域需要新的和更高精度的分子力学(MM)力场。这些新的力场引入了新的术语，描述了简单的成对力场中没有考虑的过程，例如极化和电荷转移。这些术语的引入给合理的力场设计带来了巨大的挑战，也给算法和软件带来了挑战。力场的开发部分是通过使用基于最先进的量子力学(QM)计算的能量分解方法(EDA)的信息来实现的。这项合作计划将EDA方法的进步与下一代力场的设计和验证结合在一起，以一种允许彼此促进对方影响的方式。这些方法被用来帮助合成化学家制造新药，帮助设计新的功能材料，并创造出能将化学反应加速许多数量级的新催化剂。由这一提议产生的所有方法开发都在许多广泛使用的计算化学软件包中实施。这项拟议的研究建立在三个主要推动力之上。首先，为了影响极化力场的效率，正在开发一种新的避免自洽迭代的方法，用于MM动力学，并在QM/MM计算的内环内使用。其次，这两个研究小组致力于测试和改进可极化力场中用于凝聚相模拟的MM参数，评估泡利排斥、永久静电、极化的非键参数，并探索电荷穿透、电荷转移和交换斥力的额外短程贡献模型。此外，生物分子中的扭转和溶质-溶剂相互作用也受到了关注，这方面还有很大的改进空间。在EDA工具的帮助下，这些努力得到了验证研究的补充，包括多肽中的标量偶联、斯塔克效应和三种蛋白质中的熔融曲线。具体成果包括升级的阿米巴家族的极化潜力，以及包括额外的非经典术语的更先进的模型。第三个重点是EDA方法的发展。影响MM发展的新功能包括力分解分析、将极化划分为直接项和间接项以及后者的多体分解。基于耦合团簇(CC)理论的EDA正在发展中。最后，介绍了化学键的变分EDA的新进展，包括多键和动力学关联。在开发时，先进的MM势能面方法和模型将被提供给OpenMM、OMNIA、TINKER和LibEFP，新提议的EDA能力将被提供给Q-Chem和ONETEP。Head-Gordon团队在这项研究的基础上开发了培训材料，用于计算化学社区研讨会和学校。计划通过与分子科学软件研究所(MolSSI)的互动以及Q-Chem的教学支持网页来分发这些材料

Teresa Head-Gordon and Martin Head-Gordon are supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to develop computational and theoretical models and methods that can be used to make accurate predictions for the behavior of complex molecular and bimolecular systems. This collaborative project combines the mutual development of advanced force fields and energy decomposition analysis (EDA). The field of biomolecular modeling and simulation currently relies on a simple representation of the potential energy surface of molecules based on what is known as the "pairwise additive" force field. But to design new drugs or new biomaterials the field needs new and higher accuracy molecular mechanics (MM) force fields. These new force fields introduce new terms that describe processes not considered in simple pair-wise force fields, for example, polarization and charge transfer. The introduction of such terms pose great challenges for rational force field design as well algorithmic and software challenges. The force field development is enabled in part by using information from an energy decomposition method (EDA) that is based on state-of-the art quantum mechanical (QM) calculations. This collaborative proposal is a partnership that couple's advances in EDA methods with the design and validation of next generation force fields, in a way that permits each to advance the impact of the other. These methods are used to help synthetic chemists make new drugs, to aid in the design of new functional materials, and to create new catalysts that speed up chemical reactions by many orders of magnitude. All the methods developments resulting from this proposal are being implemented in many widely used computational chemistry software packages. The proposed research is built on three main thrusts. First, to impact the efficiency of polarizable force fields, a new procedure to avoid self-consistent iterations is being developed for use in MM dynamics, and within the inner loop of QM/MM calculations. Second, the two research groups are engaged in a major effort to test and improve MM parameters in polarizable force fields for condensed phase modeling, to assess non-bonded parameters for Pauli-exclusion, permanent electrostatics, polarization, and to explore models for additional short-range contributions from charge penetration, charge transfer, and exchange repulsion. In addition, attention is paid to torsional and solute-solvent interactions in biomolecules, where there is significant scope for improvement. These efforts, informed by EDA tools, are complemented by validation studies including scalar couplings in polypeptides, Stark effects and melting curves in three proteins. Specific outcomes include an upgraded polarizable potential of the AMOEBA family, as a well as more advanced model that includes additional non-classical terms. The third thrust is the development of EDA methods. New capabilities that inform the MM developments include force decomposition analysis, partitioning of polarization into direct and indirect terms and the many-body decomposition of the latter. A soundly based EDA for coupled cluster (CC) theory is being developed. Finally, new advances in variational EDA for chemical bonds are pioneered including multiple bonds and dynamical correlation. When developed the advanced MM potential energy surfaces methodology and models will be provided to OpenMM, OMNIA, TINKER, and LibEFP, and the new proposed EDA capabilities to Q-Chem and ONETEP. The Head-Gordon groups develop training materials based on this research for use in computational chemistry community workshops and schools. Plans are to distribute these materials through interaction with the Molecular Sciences Software Institute (MolSSI) as well as through Q-Chem's instructional support web pages