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

合作研究：CDS

• 批准号: 1856162
• 负责人: Gerardo Cisneros
• 金额: $ 25.26万
• 依托单位: University of North Texas
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856162&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.

酶是专门的蛋白质，可催化生物系统中的化学反应。蛋白质周围环境的温度，压力或组成的变化以及许多其他因素可能对酶催化反应产生重大影响。通过该奖项，化学司的化学过程计划正在为北德克萨斯大学的G. Andres Cisneros博士提供资金，而来自奥斯汀大学德克萨斯大学的Pengyu Ren博士为开发了计算方法和软件，以准确预测周围型物中的效果。详细了解酶在高电动溶剂（离子液体）中的作用可能导致新的生物启发的催化剂开发用于生物技术和生物工程应用。该项目的最先进的计算方法用于研究不同带电溶液中辣根过氧化物酶（HRP）的反应机制。过氧化物酶是重要的酶，有助于预防有氧生物的氧化损伤。新开发的程序和程序源代码可自由使用，这会影响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的各种外展和指导计划中与来自代表性的少数群体的学校学生和老师互动。该项目的主要前提是，同源酶在温度中表现出最大的活性所表现出的最大活性所带来的最大活性是由于在氛围和范围内的自由贡献之间的平衡差异，即在这些自由范围之间的差异，即焓 - 渗透平衡的这种差异是由于表面残基的柔韧性差异所致。另外，对与溶剂相互作用的表面残基的柔韧性的影响可能会对活性位点发挥远距性静电作用。因此，这项研究的主要目的是应用量子力学/分子力学（QM/mm）模拟来研究高电荷离子液体（IL）溶液对焓 - 内向平衡的影响，以进行酶促催化。该项目延续了在离子液体中的Amoeba-IL（用于生物分子应用的原子多极优化能量学）的力场，并在LICHEM的QM/MM代码（分层相互作用的化学模型）中实现增强的采样方法，及其界面及其界面及其在Tinker-OpenMMOPENMM MOPENMM MOPENMM MONECULAL MENADICADERS套件中。这些工具用于计算不同IL溶液中辣根过氧化物酶的反应机理。针对各种IL解决方案系统计算的Arrhenius图确定了每个测试系统的焓 - 渗透平衡，以确定不同溶剂环境对反应途径的影响。这项工作的结果提供了对溶剂在酶催化作用的基本见解，以及表面残留灵活性对酶促反应机制的作用/影响。此外，该项目还为变形虫开发了新的方法和参数，这些方法和参数可用于广泛的科学界。该奖项反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响评估标准，被认为值得通过评估来获得支持。

项目成果

Current Status of AMOEBA–IL: A Multipolar/Polarizable Force Field for Ionic Liquids

• DOI: 10.3390/ijms21030697
• 发表时间: 2020-01
• 期刊: International Journal of Molecular Sciences
• 影响因子: 5.6
• 作者: E. A. Vázquez-Montelongo;José Enrique Vázquez-Cervantes;G. A. Cisneros

Computational investigations of selected enzymes from two iron and α-ketoglutarate-dependent families.

• DOI: 10.1039/d1cp03800a
• 发表时间: 2021-10-13
• 期刊: Physical chemistry chemical physics : PCCP
• 作者: Berger MB;Walker AR;Vázquez-Montelongo EA;Cisneros GA
• 通讯作者: Cisneros GA

Development of Imidazolium-Based Parameters for AMOEBA-IL.

• DOI: 10.1021/acs.jpcb.3c00986
• 发表时间: 2023-06
• 期刊: The journal of physical chemistry. B
• 作者: José Enrique Vázquez-Cervantes;G. Cisneros