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：变构信号传输的自由模式耦合理论 蛋白质的变构效应是由于相互作用而调节功能行为 具有效应配体或活性位点远端区域的突变是一个关键。 所有代谢控制过程的特征，生物分子机器的作用机制 以及马达、基因表达和许多其他生物现象。值得注意的是，时间框架。 变构效应约为 10-3 – 1 秒，但长度范围可能相当长（100 埃） DNA 修复蛋白 MutS）最近的评论报告了不同的例子。 在不同的例子中变构效应的实验和理论，但所有人都同意 大蛋白质中变构信号传播的分子机制仍悬而未决 最近（2020）一些可以跟踪时间演化的实验。 变构信号已被报道，但仍有许多假设需要充分解释。 关于变构如何在分子水平上发挥作用的问题已经被提出，包括 合作氨基酸残基、柔性/刚性模型、能量景观-系综理论、 和复杂的网络，所有这些都有一定的合理性，但是，每一种都已被应用于。 一类中只有一种或少数蛋白质存在阳性实例，通常不包括 统计控制也不能解释具有潜力但不会引起的配体结合或突变 变构效应（负面实例）是大蛋白质面临的一个特殊挑战。 考虑了变构信号在长距离内的传播而没有衰减。 这里所追求的假设假设有希望的远程信号传输发生在 通过与离域呼吸耦合传播的变构效应器引起的扰动 蛋白质的运动，即“自由模式耦合”（LMC）。 使用“最先进的”全技术阐明 LMC 对变构信号传导的贡献程度 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项。 该提案是变构定量诊断的开发和测试 通过 LMC 进行信号传播，应用于选定的、特征良好的 MD 仿真 所提议的 LMC-MD 研究的结果可能支持或反驳这一观点。 呼吸运动的作用，任何一个结果都会贡献有价值的新知识。 该项目将产生有关变构控制过程的新基础知识，这将 最终可用于变构药物设计。