From Theory of Energy Decomposition Analysis to Rational Force Field Design

Teresa Head-Gordon和Martin Head-Gordon获得了化学部化学理论，模型和计算方法计划的奖项，以开发可用于准确预测复杂分子和双分子系统行为的计算和理论模型和方法。 该合作项目结合了先进力场和能量分解分析（EDA）的共同发展。生物分子建模和模拟领域目前依赖于基于所谓的“成对加性”力场的分子势能面的简单表示。但是，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，描述了在简单的成对力场中没有考虑的过程，例如极化和电荷转移。这些术语的引入对合理的力场设计以及算法和软件的挑战提出了很大的挑战。 力场的发展部分是通过使用来自能量分解方法（EDA）的信息来实现的，该能量分解方法基于最先进的量子力学（QM）计算。这项合作提案是一种合作伙伴关系，将EDA方法的进步与下一代力场的设计和验证结合起来，使每一种方法都能促进另一种方法的影响。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，并创造新的催化剂，使化学反应加速许多数量级。 所有的方法的发展，从这个建议正在实施许多广泛使用的计算化学软件包。 拟议的研究建立在三个主要方面。首先，为了影响极化力场的效率，正在开发一种新的程序，以避免自洽迭代用于MM动力学，并在QM/MM计算的内环。其次，这两个研究小组正在努力测试和改进MM参数在可极化力场凝聚相建模，评估非键合参数的保利排斥，永久静电，极化，并探索模型的额外的短程贡献从电荷渗透，电荷转移，和交换排斥。此外，还注意到生物分子中的扭转和溶质-溶剂相互作用，其中有很大的改进余地。这些努力，通知EDA工具，是补充验证研究，包括标量耦合多肽，斯塔克效应和三种蛋白质的熔解曲线。具体成果 包括AMOEBA家族的升级极化势，以及包括额外的非经典项的更先进的模型。第三个推动力是EDA方法的发展。新的能力，通知MM的发展，包括力分解分析，分区的极化成直接和间接的条款和后者的多体分解。一个坚实的基础EDA耦合集团（CC）理论正在开发中。 最后介绍了化学键变分EDA的新进展，包括多重键和动力学关联。 开发完成后，先进的MM势能面方法和模型将提供给OpenMM、OMNIA、TINKER和LibEFP，新提出的EDA功能将提供给Q-Chem和ONETEP。 Head-Gordon小组根据这项研究开发了培训材料，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）的互动以及通过Q-Chem的教学支持网页分发这些材料

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