Allostery in pharmacology: thermodynamics, evolution and design.

This review focuses on basic models of allostery, the ambiguous application of the allosteric term in pharmacology illustrated by receptors, the role of thermodynamics in allosteric mechanisms, evolution and design of allostery. The initial step of ligand activation is closure of the agonist-binding cavity. Large entropy increases accompany the agonist-elicited conformational changes of pentameric ligand-gated ion channels due to cavity closure and rearrangement of transmembrane helices. The effects of point mutations on thermodynamic parameters of binding and function can reveal energetic coupling of neighbouring (and distant) amino acid residues in activation. High-order double-mutant cycle analysis and rate-equilibrium linear free-energy relationships can identify the trajectory and conformational spread of activation. Protein assembly and allostery can be deduced from colocalization and physicochemical principles. Molecular evolution has led from homooligomerization of protomers to heterotropic cooperativity and to allosteric regulation. Examples are discussed such as similar paths of protein (dis)assembly and evolution, irreversible evolution, statistical analysis of sequence homology revealing coevolution, different impacts of adaptation and evolution on hemoglobin, and the flagellar motor switch of bacteria. The driving force of dynamic allostery is associated with funnel-like free energy landscapes of protein binding and shifts in conformational fluctuations upon binding. Allostery can be designed based on our increasing knowledge of natural allosteric mechanisms and evolution. The allosteric principle has been applied for various bio/macro/molecular and signal transduction systems as well as in cognitive sciences.