Librational Mode Coupling Theory of Allosteric Signal Transmission

变构信号传输的解放模式耦合理论

• 批准号: 10360233
• 负责人: DAVID Lewis BEVERIDGE
• 金额: $ 48.25万
• 依托单位: WESLEYAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360233
• 关键词: Accounting; Active Sites; Amino Acids; Area; Behavior; Biological Models; Biological Phenomena; Biological Process; Biophysics; Breathing; Chemotaxis; Complex; Computer Simulation; Coupling; Cyclic AMP Receptor Protein; DHFR gene; DNA Repair Gene; Data; Development; Diagnostic; Dihydrofolate Reductase; Distal; Drug Design; Enzymes; Evolution; Frequencies; Gene Expression; Knowledge; Length; Ligand Binding; Ligands; Messenger RNA; Metabolic Control; Methodology; Modeling; Molecular; Molecular Conformation; Motion; Motor; Mutation; Outcome; Pathway interactions; Phosphorylation; Principal Component Analysis; Process; Proteins; Reporting; Research; Ribosomes; Role; Signal Transduction; System; TP53 gene; Testing; Time; Translating; Work; attenuation; base; experimental study; flexibility; interest; macromolecule; molecular dynamics; molecular modeling; novel; programs; prototype; success; theories; transcription factor; transmission process

Project Summary: Libratioal Mode Coupling Theory of Allosteric Signal Transmission The allosteric effect in proteins is the modulation of functional behavior due to interaction with an effector ligand or a mutation at a region distal to the active site. Allostery is a critical feature of all metabolic control processes, the mechanisms of action of biomolecular machines and motors, gene expression, and many other biological phenomena. Notably, the time frame of an allosteric effect is ~10-3 – 1 seconds, but the length scale can be quite long (100 Angstroms in the DNA repair protein, MutS). Recent reviews report diverse examples fn the state of experiment and theory of the allosteric effect in diverse examples, but all concur that the molecular mechanism of allosteric signal propagation in large proteins remains an unsettled research question. Recently (2020) some experiments that can track the time evolution of an allosteric signal have been reported, but remain to be fully interpreted. A number of hypotheses about how allostery works at the molecular level have been proposed, including pathways of cooperative amino acid residues, flexibility/rigidity models, energy landscape - ensemble theory, and complex networks, all of which have some plausibility. However, each has been applied to positive instances in only one or just a few proteins in a class, and typically do not include statistical controls nor explain ligand binding or mutations which have potential but do not elicit an allosteric effect (negative instances). A particular challenge with large proteins has been accounting for the propagation of allosteric signals over long range without attenuation. A promising hypothesis pursued here postulates that long-range signal transmission occurs as an allosteric effector-induced perturbation transmitted via coupling with the delocalized breathing motions of a protein, i.e. “librational mode coupling” (LMC). The proposed research involves elucidating the extent to which LMC contributes to allosteric signaling using “state-of-the-art" all- atom molecular dynamics (MD) computer simulations together with our LMC analysis, considering both motional and energy options for obtaining modes. The specific objective of this proposal is the development and testing of a quantitative metric diagnostic of allosteric signal propagation via LMC as applied to MD simulations on selected, well-characterized allosteric proteins. The results of the proposed LMC-MD studies may either support or refute the role of breathing motions, with either outcome contributing valuable new knowledge. Success of this project will result in new fundamental knowledge about allosteric control processes that will be ultimately useful in allosteric drug design.

项目摘要：变构信号传输的库模式耦合理论 蛋白质的变构作用是由于相互作用而调节功能行为 带有效应子配体或活动位点远端区域的突变。变构是关键 所有代谢控制过程的特征，生物分子机的作用机理 和电动机，基因表达以及许多其他生物学现象。值得注意的是，时间范围 变构效应是〜10-3 - 1秒，但长度尺度可能很长（100埃 在DNA修复蛋白中，muts）。最近的评论报告各种例子 在潜水员中的变构作用的实验和理论，但都同意 大蛋白质中变构信号传播的分子机制仍然是未解决的 研究问题。最近（2020年）一些实验可以跟踪 已经报道了变构信号，但仍待完全解释。许多假设 关于在分子水平上的变构作用，包括 合作氨基酸的保留，柔韧性/刚性模型，能量景观 - 合奏理论， 和复杂的网络，所有这些都具有一定的合理性。但是，每个都应用于 在班级中仅使用一种或仅几个蛋白质的积极实例，通常不包括 统计控制也不解释具有潜力但不引起的配体结合或突变 变构效应（负面实例）。大蛋白的一个特殊挑战是 考虑到远距离的变构信号在没有衰减的情况下的传播。一个 这里提出的有希望的假设假设延长信号传递是作为一个 变构效应诱导的扰动通过与DELEACALIZED呼吸耦合传播 蛋白质的运动，即“库模式耦合”（LMC）。拟议的研究涉及 阐明LMC使用“最先进的” all- 原子分子动力学（MD）计算机模拟以及我们的LMC分析， 考虑获得模式的运动和能量选择。的具体目标 该建议是变构定量度量诊断的开发和测试 通过LMC进行信号传播，以适用于选定的，良好的MD模拟 变构蛋白。拟议的LMC-MD研究的结果可以支持或反驳 呼吸动作的作用，两种结果都促进了价值新知识。成功 该项目将导致有关变构控制过程的新基本知识 最终在变构药物设计中有用。