Structure-Based Statistical Mechanical Model Accounts for the Causality and Energetics of Allosteric Communication

Allostery is one of the pervasive mechanisms through which proteins in living systems carry out enzymatic activity, cell signaling, and metabolism control. Effective modeling of the protein function regulation requires a synthesis of the thermodynamic and structural views of allostery. We present here a structure-based statistical mechanical model of allostery, allowing one to observe causality of communication between regulatory and functional sites, and to estimate per residue free energy changes. Based on the consideration of ligand free and ligand bound systems in the context of a harmonic model, corresponding sets of characteristic normal modes are obtained and used as inputs for an allosteric potential. This potential quantifies the mean work exerted on a residue due to the local motion of its neighbors. Subsequently, in a statistical mechanical framework the entropic contribution to allosteric free energy of a residue is directly calculated from the comparison of conformational ensembles in the ligand free and ligand bound systems. As a result, this method provides a systematic approach for analyzing the energetics of allosteric communication based on a single structure. The feasibility of the approach was tested on a variety of allosteric proteins, heterogeneous in terms of size, topology and degree of oligomerization. The allosteric free energy calculations show the diversity of ways and complexity of scenarios existing in the phenomenology of allosteric causality and communication. The presented model is a step forward in developing the computational techniques aimed at detecting allosteric sites and obtaining the discriminative power between agonistic and antagonistic effectors, which are among the major goals in allosteric drug design.别构效应（allostery）是生命系统中蛋白质执行酶促活性、细胞信号转导与代谢调控的普遍机制之一。对蛋白质功能调控开展有效建模，需要整合别构效应的热力学与结构双重视角。本文提出一种基于结构的别构效应统计力学模型，该模型可用于观测调控位点与功能位点间通信的因果关系，并估算单个残基的自由能变化。研究基于简谐模型框架下无配体与配体结合体系的分析，得到对应的特征简正模集合，并将其作为别构势能的输入参数。该别构势能可量化因邻近残基局部运动而施加在目标残基上的平均功。随后，在统计力学框架中，可通过对比无配体与配体结合体系的构象系综，直接计算残基别构自由能的熵贡献。综上，本方法为基于单一结构分析别构通信的能量学特征提供了系统性研究途径。该方法的可行性已在一系列别构蛋白质上得到验证，这些蛋白质在尺寸、拓扑结构与寡聚化程度上均存在异质性。别构自由能的计算结果揭示了别构因果关系与通信现象学中多样的作用方式与复杂的作用场景。本模型为开发用于识别别构位点、区分激动剂与拮抗剂效应物的计算技术迈出了关键一步，而上述目标正是别构药物设计的核心方向之一。