CDS&E: Theoretical Models for Potential Energy Landscapes of Challenging Chemical Systems

David Sherrill获得了化学部化学理论、模型和计算方法项目以及计算科学和数据科学与工程项目的奖励，以开发用于研究非共价相互作用的计算方法、算法和软件。非共价相互作用是蛋白质折叠、药物对接、晶体包装和溶剂化的核心。最近的实验提供了有机模型系统的详细数据，旨在分离和量化溶液中单个非共价相互作用，但如果没有理论的帮助，它们仍然很难理解。该项目旨在揭示影响这些实验有机系统中非共价相互作用的各种因素。Sherrill小组正在(1)使用密度拟合技术开发更快的密度泛函理论（DFT）几何优化和频率分析算法。(2)使用直接取自蛋白质数据库（PDB）的测试用例，将可用的基准质量非共价相互作用能集从几百个扩展到几千个。这些数据对于验证和参数化非共价相互作用的理论模型至关重要。(3)结合密度拟合、自然轨道和秩降技术，识别耦合聚类理论中的协同逼近，以加速目标(2)中的计算。(4)对CH/pi和pi-pi相互作用的实验模型复合物进行详细研究，以更好地了解这些相互作用，它们如何在溶液中运作，以及如何更有效地建模。谢里尔小组开发并使用计算方法来更好地理解分子之间的非键相互作用。这种相互作用控制着药物如何找到它们的靶标以及分子晶体如何形成。因此，本研究为合理的药物设计和晶体工程的发展提供了有用的知识。该项目通过(a)改进计算机算法以更快地计算相互作用，以及(b)生成大型高质量基准数据数据库，可用于测试和改进非键接触的新理论模型，为此类非键接触的建模提供了改进的理论和计算方法。基准数据将通过一个门户网站公开提供。开发的软件将在开源许可下免费发布。这个项目不仅训练了学生如何使用分子建模软件，也训练了学生如何编写分子建模软件。

David Sherrill is supported by an award from the Chemical Theory, Models and Computational Methods program in the Chemistry Division and the Computational Science and Data-enabled Science and Engineering Program to develop computational methods, algorithms and software for studying non-covalent interactions. Non-covalent interactions are central to protein folding, drug docking, crystal packing, and solvation. Recent experiments provide detailed data on organic model systems meant to isolate and quantify individual non-covalent interactions in solution, yet they remain hard to understand without the aid of theory. This project seeks to unravel the various factors influencing non-covalent interactions in these experimental organic systems. The Sherrill group is (1) Developing faster algorithms for density functional theory (DFT) geometry optimization and frequency analysis, using density fitting techniques.(2) Expanding the available set of benchmark-quality non-covalent interaction energies from a few hundred to several thousand, using test cases taken directly from the Protein Data Bank (PDB). This data is critical for validating and parameterizing theoretical models of non-covalent interactions.(3) Identifying synergistic approximations in coupled-cluster theory to accelerate the computations in Goal (2), using combinations of density-fitting, natural orbitals, and rank-reduction techniques.(4) Performing detailed studies of experimental model complexes of CH/pi and pi-pi interactions to better understand these interactions, how they operate in solution, and how they might be more effectively modeled.The Sherrill group develops and uses computational methods to better understand non-bonded interactions between molecules. Such interactions control how drugs find their targets and how molecular crystals form. Hence, this research provides knowledge useful for advances in rational drug design and crystal engineering. This project provides improved theoretical and computational methods for modeling such non-bonded interactions through (a) improved computer algorithms to compute interactions more quickly, and (b) generation of a large database of high-quality benchmark data that can be used to test and improve new theoretical models of non-bonded contacts. The benchmark data will be made publicly available through a web portal. The software developed will be freely released under an open-source license. This project provides training for students not only in how to use molecular modeling software, but also in how to write molecular modeling software.