Coupled Protons and Electrons in Biological Systems

生物系统中的质子和电子耦合

基本信息

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
项目类别：
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

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

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项目摘要

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。