Librational Mode Coupling Theory of Allosteric Signal Transmission

变构信号传输的库模式耦合理论研究综述 蛋白质中的变构效应是由于相互作用而对功能行为的调节 在活性部位的远端区域带有效应器配体或突变。变构是一个至关重要的因素 所有代谢控制过程的特点，生物分子机器的作用机制 和马达，基因表达，以及许多其他生物现象。值得注意的是， 变构效应约为10-3-1秒，但长度标度可以相当长(100埃 在DNA修复蛋白中，MutS)。最近的审查报告了不同的例子。 变构效应在不同例子中的实验和理论，但都同意 变构信号在大蛋白中传播的分子机制尚不清楚 研究问题。最近(2020)一些实验可以跟踪一个人的时间演化 变构信号已被报道，但仍未完全解释。一系列假设 关于变构是如何在分子水平上起作用的，包括 合作氨基酸残基，柔性/刚性模型，能量景观-集合理论， 以及复杂的网络，所有这些都有一些似是而非的可能性。但是，每种方法都已应用于 在一个类别中只有一个或几个蛋白质中出现阳性实例，通常不包括 统计控制也不能解释配基结合或有潜力但不能引发的突变 变构效应(负例)。对于大型蛋白质来说，一个特别的挑战是 考虑到变构信号在没有衰减的情况下在远距离传播。一个 这里所追求的有希望的假说假设，远程信号的传输是作为一种 变构效应诱导的微扰通过与离域呼吸的耦合传递 蛋白质的运动，即“振动模耦合”(LMC)。建议的研究包括 用最新技术阐明LMC在变构信号中的作用 原子分子动力学(MD)计算机模拟与我们的LMC分析相结合， 考虑获得模式的运动和能量选项。的具体目标 这项建议是开发和测试变构的定量计量诊断 通过LMC的信号传播在选定的、特征良好的MD模拟中的应用 变构蛋白。拟议的LMC-MD研究结果可能支持也可能驳斥 呼吸运动的作用，这两种结果都提供了有价值的新知识。取得的成功 该项目将产生关于变构控制过程的新的基础知识，将 在变构药物设计中最终是有用的。

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.