Computational Analysis of Enzyme Catalysis and Regulation

酶催化与调控的计算分析

• 批准号: 10206585
• 负责人: Qiang Cui
• 金额: $ 29.56万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206585
• 关键词: Active Sites; Allosteric Regulation; Catalysis; Chemicals; Computer Analysis; Computing Methodologies; Coupled; Coupling; Crystallography; Diabetes Mellitus; Directed Molecular Evolution; Distal; Drug Design; Enzymes; Equilibrium; Event; Free Energy; Insulin Resistance; Ions; Knowledge; Machine Learning; Malignant Neoplasms; Membrane; Metals; Modernization; Modification; Molecular Conformation; Mutation; Nature; Nucleic Acids; Penetration; Peripheral; Positioning Attribute; Process; Proteins; Reaction; Regulation; Research; Sampling; Specificity; Speed; Techniques; Time; Tweens; Water; computerized tools; design; enzyme mechanism; human disease; insight; lipid metabolism; method development; mutation screening; novel; recruit; transcription factor

Project Summary: It is of great fundamental and biomedical importance to understand the physical princi- ples that govern the coupling between the chemical step in a biomolecule and other events, such as penetration of water molecules into the active site, recruitment of transient metal ions, or conformational rearrangements near and afar. This is a challenging task, however, due to the intrinsic multi-scale nature of the problem. As a result, our understanding in factors that dictate the efficiency and specificity of enzyme catalysis remains in- complete, especially regarding contributions beyond the active site; this knowledge gap has greatly limited our ability to design highly efficient enzymes de novo. Motivated by these considerations, the overarching theme of our research is to develop and apply multi-scale computational methods to reveal the underlying mechanism of enzyme catalysis at an atomic level, with a particular emphasis on establishing to what degree the chem- ical step is coupled with other processes proximal or distal to the active site. Specifically, we aim to develop an efficient QM/MM framework to compute free energy profiles of enzyme reactions with a good balance of computational speed and accuracy; further integration with enhanced sampling approaches, machine learning techniques and modern computational hardwares enables us to gain insights into the nature of coupling be- tween the chemical step and other events during the functional cycle. Accordingly, we are in a unique position to pursue several lines of exciting applications, which include the mechanism and impact of transient metal ion recruiting in nucleic acid processing enzymes, the catalytic and regulatory mechanism of peripheral membrane enzymes, and systemic analysis of allosteric coupling in a transcription factor; an emerging research direction is to explore the interplay of stability, catalytic activity, and allostery during continuous directed evolution. Our project integrates computational method developments with applications inspired by recent experimental ad- vances, such as time-resolved crystallography, deep mutational scanning and continuous directed evolution. The research efforts will lead to novel computational tools and mechanistic insights into the regulatory mech- anisms of enzymes by processes either near or remote from the active site. Thus the project will have both fundamental impacts and implications for better design strategies for catalysis and allostery in biomolecules.

项目摘要：了解物理原理是非常重要的和生物医学的重要性 在生物分子和其他事件（例如渗透）中控制化学步骤之间耦合的元素 水分子进入活性位点，瞬时金属离子或构象重排 附近和远处。但是，由于问题的内在多尺度性质，这是一项挑战任务。作为 结果，我们对决定效率和特定酶催化的特定城市的理解仍然存在。 完整，尤其是有关活动现场以外的贡献；这个知识差距极大地限制了我们的 能够设计从头开始的高度有效酶。受这些考虑的激励，这是总体主题 我们的研究是开发和应用多尺度计算方法来揭示基本机制 在原子水平上酶催化的酶，特别强调建立化学 ICAL步骤与活动位点近端或远端的其他过程相结合。特定的，我们旨在发展 有效的QM/mm框架，以良好的平衡计算酶反应的自由能力纤维 计算速度和准确性；与增强的采样方法，机器学习进一步集成 技术和现代计算硬件使我们能够深入了解耦合的性质 在功能周期中鸣叫化学步骤和其他事件。彼此之间，我们处于独特的位置 购买几行令人兴奋的应用程序，其中包括瞬态金属离子的机制和影响 在核酸加工酶，周围膜的催化和调节机制中招募 酶和转录因子中变构耦合的全身分析；新兴的研究方向 是在连续的定向演化过程中探索稳定性，催化活性和变构的相互作用。我们的 项目集成计算方法的开发与受到最新实验性ad-启发的应用 Vances，例如时间分辨的晶体学，深突变扫描和连续的定向进化。 研究工作将导致新的计算工具和机械洞察力，对调节机械 - 酶的氮通过在附近或远离活动位置的过程中进行的酶。该项目将两者都有 对催化和生物分子的变构的更好设计策略的基本影响和影响。