Collaborative Research: CDS&E: Computational Investigation of Solvent Effects on Enzyme Catalysis

合作研究：CDS

• 批准号: 1856173
• 负责人: Pengyu Ren
• 金额: $ 25.64万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856173&HistoricalAwards=false
• 关键词: Collaborative; Research; CDS&E; Computational; Investigation

Enzymes are specialized proteins that catalyze chemical reactions in biological systems. Changes in temperature, pressure, or composition of the environment surrounding the protein, among many other factors, can have significant effects on enzyme catalyzed reactions. With this award, the Chemistry of Life Processes Program of the Chemistry Division is funding Dr. G. Andres Cisneros from the University of North Texas and Dr. Pengyu Ren from the University of Texas at Austin to develop computational methods and software to accurately predict the effects that charges in the surrounding solvent have on enzymatic catalysis. Detailed understandings for how enzymes function in highly charged solvents (ionic liquids) potentially lead to the development of new bio-inspired catalysts for biotechnology and bioengineering applications. The state-of-the-art computational methods from this project are used to investigate the reaction mechanisms of horseradish peroxidase (HRP) in different charged solutions. Peroxidases are important enzymes that help prevent oxidative damage in aerobic organisms. The newly developed methods and source codes for programs are made freely available, which impact the ability of the scientific community to predict the behavior of enzymes in a variety of environments. In addition, the project engages school students and teachers from underrepresented minority groups in the sciences through various outreach and mentoring programs at the two participating institutions.The main premise of this project is that differences in temperatures at which homologous enzymes show maximum activity arise from differences in the balance between enthalpic and entropic contributions to the free energies of activation, even when these free energies are similar. This difference in enthalpic-entropic balance is due to differences in flexibility of surface residues. Alternatively, effects on the flexibility of surface residues from interactions with the solvent may exert long range-electrostatic effects on the active sites. Therefore, the main goal of this study is to apply quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the effect of highly charged ionic liquid (IL) solutions on the enthalpic-entropic balance for enzymatic catalysis. This project continues the development of the AMOEBA-IL (atomic multipole optimized energetics for biomolecular applications in ionic liquids) force field and implements enhanced sampling methods in the QM/MM code of the LICHEM (Layered Interacting Chemical Models) package and its interface to TINKER-OpenMM molecular mechanics/dynamics sortware package. These tools are used to computationally model the reaction mechanism of horseradish peroxidase in different IL solutions. Arrhenius plots calculated for the various IL solution systems determine the enthalpic-entropic balance for each tested system to ascertain the effect of the different solvent environments on the reaction pathway. Results from this work provide fundamental insights into the role of solvents on enzyme catalysis and the role/impact of surface-residue flexibility on enzymatic reaction mechanisms. Additionally, this project develops new methods and parameters for AMOEBA, and these are made available to the broad scientific community.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

酶是催化生物系统中化学反应的专门蛋白质。温度、压力或蛋白质周围环境的组成的变化以及许多其他因素可以对酶催化反应产生显著影响。有了这个奖项，化学部的生命过程化学计划正在资助G。来自北德克萨斯大学的Andres西斯内罗斯和来自德克萨斯大学奥斯汀分校的Pengyu Ren博士开发计算方法和软件，以准确预测周围溶剂中的电荷对酶催化的影响。对酶在高电荷溶剂（离子液体）中如何发挥作用的详细了解可能会导致开发用于生物技术和生物工程应用的新的生物启发催化剂。本计画利用最先进的计算方法研究辣根过氧化物酶（HRP）在不同电荷溶液中的反应机制。过氧化物酶是重要的酶，有助于防止有氧生物体中的氧化损伤。新开发的方法和程序源代码可以免费获得，这影响了科学界预测酶在各种环境中的行为的能力。此外，该项目通过在两个参与机构开展的各种推广和指导方案，吸引来自科学界代表性不足的少数群体的学生和教师参与。该项目的主要前提是，同源酶显示最大活性的温度差异是由对活化自由能的熵和熵贡献之间的平衡差异引起的，即使这些自由能是相似的。这种热力学-熵平衡的差异是由于表面残基的柔性的差异。或者，与溶剂的相互作用对表面残基的柔性的影响可能会对活性位点产生长程静电效应。因此，本研究的主要目标是应用量子力学/分子力学（QM/MM）模拟研究高电荷离子液体（IL）溶液对酶催化的热力学-熵平衡的影响。该项目继续开发AMOEBA-IL（离子液体中生物分子应用的原子多极优化能量学）力场，并在LICHEM（分层相互作用化学模型）包的QM/MM代码及其与TINKER-OpenMM分子力学/动力学软件包的接口中实现增强的采样方法。这些工具被用来计算模型的辣根过氧化物酶在不同的IL解决方案的反应机制。为各种IL溶液系统计算的Arrhenius图确定了每个测试系统的热力学-熵平衡，以确定不同溶剂环境对反应途径的影响。从这项工作的结果提供了基本的见解的作用，溶剂对酶催化和酶反应机制的作用/影响的表面残基的灵活性。此外，该项目还为AMOEBA开发了新的方法和参数，并将其提供给广大的科学界。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface

• DOI: 10.1021/acs.jpclett.1c01460
• 发表时间: 2021-07-01
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY LETTERS
• 影响因子: 5.7
• 作者: El Ahdab, Dina;Lagardere, Louis;Piquemal, Jean-Philip
• 通讯作者: Piquemal, Jean-Philip