Design and application of robust and efficient QM/MM free energy simulation methods for biomolecular systems

生物分子系统稳健高效的 QM/MM 自由能模拟方法的设计与应用

• 批准号: 10260512
• 负责人: Henry Lee Woodcock III
• 金额: $ 30.28万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260512
• 关键词: Accounting; Award; Behavior; Binding; Biochemistry; Biological Process; Catalysis; Chemicals; Chemistry; Complex; Coupled; Development; Electrostatics; Ensure; Environment; Enzymes; Free Energy; Freedom; Goals; Hybrids; Hydrogen Bonding; ImProv; Improve Access; Lactamase; Ligand Binding; Ligands; Mechanics; Methodology; Methods; Molecular; Molecular Conformation; Motion; Nobel Prize; Performance; Pharmaceutical Preparations; Price; Process; Protocols documentation; Reaction; Sampling; Scheme; Structure; Substrate Interaction; System; Techniques; Thermodynamics; Work; chemical reaction; computational chemistry; cost; design; enzyme substrate; flexibility; improved; inhibitor/antagonist; multi-scale modeling; neural network; novel; quantum; receptor; simulation; tautomer; technique development; theories; tool

Project Summary / Abstract To accurately compute free energies of complex biomolecular systems there are two key prerequisites: the accurate description of inter- and intramolecular interactions, and adequate sampling of all relevant conformational degrees of freedom. Include the possibility that conformational dynamics may be coupled to complex electronic processes or chemical reactions, where quantum mechanical (QM) methods are needed, and this task becomes extremely daunt- ing. Currently, whenever accurate computations of biomolecular systems are essential, the tool of choice is hybrid quantum mechanical / molecular mechanical (QM/MM) calculations, however, the application of these techniques to free energy simulations (FES) is far from common. Herein, we aim to develop a set of robust, efficient, and accurate new techniques that will make the application of QM/MM FES nearly routine. These methods will be subsequently ap- plied to study two classes of biomolecular applications that present extreme challenges to current techniques. Namely, the accurate computation of (1) absolute pKa as a function of ligand binding and reaction (e.g., accounting for tran- sient interactions), and (2) free energy differences of binding as a function of tautomerism. The scientific results will be closely tied to activities aimed at improving access to these advanced techniques.

项目概要/摘要 为了准确计算复杂生物分子系统的自由能，有两个关键先决条件： 分子间和分子内相互作用的描述，以及所有相关构象程度的充分采样 包括构象动力学可能与复杂的电子过程耦合的可能性。 化学反应，其中需要量子力学（QM）方法，而这项任务变得极其艰巨—— 目前，只要需要精确计算生物分子系统，就会选择混合工具。 然而，量子力学/分子力学（QM/MM）计算，这些技术的应用 自由能模拟 (FES) 并不常见，我们的目标是开发一套强大、高效且准确的模拟。 新技术将使 QM/MM FES 的应用几乎成为常态。 致力于研究对当前技术提出极大挑战的两类生物分子应用。 准确计算 (1) 绝对 pKa 作为配体结合和反应的函数（例如，考虑反式 sient相互作用），以及（2）作为互变异构函数的结合自由能差异。 与旨在改善获得这些先进技术的活动密切相关。

项目成果

Hierarchical Markov State Model Building to Describe Molecular Processes.

建立描述分子过程的分层马尔可夫状态模型。

• 发表时间: 2020-03-10
• 作者: Wolfe, David K;Persichetti, Joseph R;Sharma, Ajeet K;Hudson, Phillip S;Woodcock, H Lee;O'Brien, Edward P
• 通讯作者: O'Brien, Edward P

Characterization and engineering of a two-enzyme system for plastics depolymerization.

塑料解聚双酶系统的表征和工程。

• 发表时间: 2020
• 影响因子: 11.1
• 作者: Knott, Brandon C;Erickson, Erika;Allen, Mark D;Gado, Japheth E;Graham, Rosie;Kearns, Fiona L;Pardo, Isabel;Topuzlu, Ece;Anderson, Jared J;Austin, Harry P;Dominick, Graham;Johnson, Christopher W;Rorrer, Nicholas A;Szostkiewicz, Caralyn J;Copi
• 通讯作者: Copi

Use of Interaction Energies in QM/MM Free Energy Simulations.

在 QM/MM 自由能模拟中使用相互作用能量。

• 发表时间: 2019-08-13
• 作者: Hudson, Phillip S;Woodcock, H Lee;Boresch, Stefan
• 通讯作者: Boresch, Stefan

Mechanism of proton transfer in class A β-lactamase catalysis and inhibition by avibactam.

A 类β-内酰胺酶催化和阿维巴坦抑制中的质子转移机制。

• 发表时间: 2020
• 影响因子: 11.1
• 作者: Pemberton, Orville A;Noor, Radwan E;Kumar M V, Vasantha;Sanishvili, Ruslan;Kemp, M Trent;Kearns, Fiona L;Woodcock, H Lee;Gelis, Ioannis;Chen, Yu
• 通讯作者: Chen, Yu

Not Drug-like, but Like Drugs: Cnidaria Natural Products.

不是类药物，而是像药物：刺胞动物天然产物。

• 发表时间: 2021-12-30
• 影响因子: 5.4
• 作者: Laguionie;Allcock, A Louise;Baker, Bill J;Conneely, Ellie;Dietrick, Sarah G;Kearns, Fiona;McKeever, Kate;Young, Ryan M;Sierra, Connor A;Soldatou, Sylvia;Woodcock, H Lee;Johnson, Mark P
• 通讯作者: Johnson, Mark P