Abdelsattar Abdallah S, Mansour Youssef, Aboul-Ela Fareed
Center for X-Ray Determination of the Structure of Matter, Zewail City of Science and Technology, Ahmed Zewail Road, October Gardens, 12578, Giza, Egypt.
Chembiochem. 2021 May 4;22(9):1499-1516. doi: 10.1002/cbic.202000695. Epub 2021 Feb 10.
The effects of ligand binding on biomolecular conformation are crucial in drug design, enzyme mechanisms, the regulation of gene expression, and other biological processes. Descriptive models such as "lock and key", "induced fit", and "conformation selection" are common ways to interpret such interactions. Another historical model, linked equilibria, proposes that the free-energy landscape (FEL) is perturbed by the addition of ligand binding energy for the bound population of biomolecules. This principle leads to a unified, quantitative theory of ligand-induced conformation change, building upon the FEL concept. We call the map of binding free energy over biomolecular conformational space the "binding affinity landscape" (BAL). The perturbed FEL predicts/explains ligand-induced conformational changes conforming to all common descriptive models. We review recent experimental and computational studies that exemplify the perturbed FEL, with emphasis on RNA. This way of understanding ligand-induced conformation dynamics motivates new experimental and theoretical approaches to ligand design, structural biology and systems biology.
配体结合对生物分子构象的影响在药物设计、酶机制、基因表达调控及其他生物过程中至关重要。诸如“锁钥模型”“诱导契合模型”和“构象选择模型”等描述性模型是解释此类相互作用的常用方式。另一个历史模型——连锁平衡模型，提出自由能景观（FEL）会因生物分子结合态群体的配体结合能的加入而受到扰动。基于FEL概念，这一原理引出了一个关于配体诱导构象变化的统一的定量理论。我们将生物分子构象空间上的结合自由能图谱称为“结合亲和力景观”（BAL）。受扰动的FEL预测/解释了符合所有常见描述性模型的配体诱导的构象变化。我们综述了近期例证受扰动FEL的实验和计算研究，重点是RNA。这种理解配体诱导构象动力学的方式推动了配体设计、结构生物学和系统生物学方面新的实验和理论方法的发展。
