Coupled Protons and Electrons in Biological Systems

生物系统中的质子和电子耦合

• 批准号: 10321617
• 负责人: SHARON HAMMES-SCHIFFER
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321617
• 关键词: Biochemical; Biochemical Process; Biological; Biological Models; Biological Process; Biomimetics; Cell Respiration; Complex; Coupled; Cryoelectron Microscopy; DNA biosynthesis; Data; Drug Design; Electron Transport; Electrons; Electrostatics; Environment; Enzymes; Equilibrium; Goals; Hydrogen; Individual; Kinetics; Length; Measurement; Methods; Modeling; Molecular Conformation; Motion; Movement; Nuclear; Nucleotides; Organism; Oxides; Pathway interactions; Play; Process; Protein Conformation; Protein Engineering; Proteins; Protons; Reaction; Ribonucleotide Reductase; Role; Series; Solvents; Structure; Theoretical Studies; Thermodynamics; Time; Tryptophan; Tyrosine; Work; alpha helix; biological systems; insight; molecular dynamics; multi-scale modeling; optogenetics; protein complex; prototype; quantum; quantum chemistry; repaired; theories

Project Summary/Abstract Controlling the movement of electrons and protons is critical for a wide range of biological processes, including cellular respiration, DNA biosynthesis, and photoreception used for optogenetics. Many of these processes are driven by the formation of tyrosine or tryptophan radical species via proton-coupled electron transfer (PCET). An elementary PCET reaction involves the transfer of one electron and one proton, but more complex PCET processes involve the transfer of multiple electrons and protons. The Hammes-Schiffer group has developed a general PCET theory enabling the calculation of rate constants and has applied this theory to biomimetic model systems and to elementary PCET in an enzyme. Simulating more complex biological PCET processes is challenging because of the significance of hydrogen tunneling and conformational motions, as well as key contributions from multiple time and length scales. A major goal of this proposal is to develop a multiscale modeling approach that describes the individual PCET steps, including the electronic and nuclear quantum effects, as well as the key conformational changes coupled to them. Quantum chemistry and molecular dynamics methods will be used to compute the input quantities to the PCET theory. The calculated rate constants for individual PCET reactions and protein conformational changes will serve as input into microkinetic models to enable the complete description of complex multi-electron, multi-proton biological processes. This multiscale modeling approach will be closely connected to experimental data, relying on atomic-level structures and thermodynamic and kinetic measurements. Initially this approach will be applied to PCET in the well-defined, controlled protein environment of the α3X proteins, which consist of three alpha helices with a single interior tyrosine or tryptophan that can be oxidized electrochemically. This approach will be expanded to explore multi- electron, multi-proton reactions in the more complex protein environment of ribonucleotide reductase (RNR). This enzyme catalyzes the conversion of nucleotides to deoxynucleotides, thereby maintaining the nucleotide pool balance required for effective DNA synthesis, replication, and repair. In addition to its biochemical importance, RNR serves as a prototype for multi-step biological PCET. The long-range radical translocation over ~35 Å in RNR is proposed to occur via a series of PCET steps involving tyrosine and tryptophan residues, as well as significant conformational changes. A recently solved cryo-EM structure of the active complex resolves the entire PCET pathway and provides an opportunity for theoretical studies. This work will elucidate the impact of the protein electrostatic environment, solvent accessibility, and conformational motions on PCET. It will also provide insights into how individual PCET steps are coupled to each other and to protein conformational motions and what determines the order of the steps and the overall rate. Discovering the factors that impact biological PCET is vital for understanding and controlling a wide range of essential biochemical processes. These fundamental insights may also have broader implications for protein design and optogenetics.

项目摘要/摘要 控制电子和质子的运动对于广泛的生物过程至关重要，包括 细胞呼吸，DNA生物合成和用于光遗传学的光感受。这些过程中有许多是 由酪氨酸或色氨酸自由基通过质子偶联电子转移（PCET）驱动。一个 基本PCET反应涉及一个电子和一个质子的转移，但更复杂的PCET 过程涉及多个电子和质子的转移。 Hammes-Schiffer组已开发 一般的PCET理论实现了速率常数的计算，并将该理论应用于仿生模型 系统和酶中的基本PCET。模拟更复杂的生物PCET过程是 具有挑战性，因为氢隧穿和构象运动的重要性以及关键 来自多个时间和长度尺度的贡献。该提案的主要目标是开发多尺度 描述各个PCET步骤的建模方法，包括电子和核量子 效果以及关键的会议变化与它们结合。量子化学和分子动力学 方法将用于计算PCET理论的输入量。计算的费率常数 单个PCET反应和蛋白质构象变化将作为对微动模型的输入 启用复杂的多电子，多原子生物学过程的完整描述。这个多尺度 建模方法将与实验数据紧密连接，依靠原子级结构和 热力学和动力学测量。最初，此方法将应用于定义明确的PCET α3X蛋白的受控蛋白质环境，该蛋白质由三个α螺旋组成 可以用电化学氧化的酪氨酸或色氨酸。该方法将扩展以探索多 电子，核糖核苷酸还原（RNR）中更复杂的蛋白质环境中的多质子反应。 这种酶催化了核苷酸向脱氧核苷酸的转化，从而维持核苷酸 有效的DNA合成，复制和修复所需的池平衡。除了生化 重要的是，RNR是多步生物PCET的原型。远程激进的易位 提议在RNR中〜35Å通过一系列涉及酪氨酸和色氨酸残留物的PCET步骤，如 以及重大构象变化。活跃复合物的最近解决的冷冻EM结构解决了 整个PCET途径，为理论研究提供了机会。这项工作将阐明影响 蛋白质静电环境，溶剂可及性和PCET上的构象运动。它也会 提供有关如何相互耦合和蛋白质构象运动的见解 以及决定步骤顺序和整体速率的是什么。发现影响生物学的因素 PCET对于理解和控制广泛的基本生化过程至关重要。这些 基本见解也可能对蛋白质设计和光遗传学具有更广泛的影响。