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.

项目概要：变构信号传递的自由模式耦合理论 蛋白质中的变构效应是由于相互作用而引起的功能行为的调节 在活性位点的远端区域具有效应配体或突变。Allostery是一个关键的 所有代谢控制过程的特征，生物分子机器的作用机制 基因表达和许多其他生物现象。值得注意的是， 变构效应为~10-3 - 1秒，但长度尺度可以相当长（100埃 DNA修复蛋白MutS）。最近的评论报告了各种各样的例子， 实验和理论的变构效应在不同的例子，但都同意， 变构信号在大蛋白中传播的分子机制仍然是一个未解决的问题。 研究问题。最近（2020年），一些实验可以跟踪一个 已经报道了变构信号，但仍有待充分解释。一些假设 关于变构如何在分子水平上起作用的研究已经提出，包括 协同氨基酸残基，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可扩展性。但是，每一个都适用于 在一类蛋白质中仅一种或仅几种蛋白质中存在阳性实例，并且通常不包括 统计学控制也不能解释配体结合或突变，其具有潜在的但不引起 变构效应（负面实例）。大蛋白质的一个特殊挑战是 这说明了变构信号在长距离上的传播而没有衰减。一 这里所追求的一个有希望的假设假设是，长距离信号传输是作为一种 通过与离域呼吸耦合传递的变构效应诱导的扰动 蛋白质的运动，即“振动模式耦合”（LMC）。拟议的研究涉及 阐明LMC在多大程度上有助于变构信号传导使用“国家的最先进的”所有- 原子分子动力学（MD）计算机模拟与我们的LMC分析， 考虑用于获得模式的运动和能量选项。的具体目标 该建议是开发和测试变构的定量度量诊断， 信号传播通过LMC适用于MD模拟选定的，良好的特点 变构蛋白拟议的LMC-MD研究的结果可能支持或反驳 呼吸运动的作用，任何一个结果都有助于有价值的新知识。成功 该项目将导致有关变构控制过程的新的基础知识， 最终可用于变构药物设计。