A comprehensive ensemble model for comparing the allosteric effect of ordered and disordered proteins

Abstract

AbstractIntrinsically disordered proteins/regions (IDPs/IDRs) are prevalent in allosteric regulation. It was previously thought that intrinsic disorder is favorable for maximizing the allosteric coupling. Here, we propose a comprehensive ensemble model to compare the roles of both order-order transition and order-disorder transition in allosteric effect. It is revealed that the MWC pathway (order-order transition) has a higher probability than the EAM pathway (disorder-order transition) in allostery, suggesting a complicated role of IDPs/IDRs in regulatory proteins. In addition, an analytic formula for the maximal allosteric coupling response is obtained, which shows that too stable or too unstable state is unfavorable to endow allostery, and is thus helpful for rational design of allosteric drugs.Author SummaryAllosteric effect is an important regulation mechanism in biological processes, where the binding of a ligand at one site of a protein influences the function of a distinct site. Conventionally, allostery was thought to originate from structural transition. However, in recent years, intrinsically disordered proteins (IDPs) were found to be widely involved in allosteric regulation in despite of their lack of ordered structure under physiological condition. It is still a mystery why IDPs are prevalent in allosteric proteins and how they differ from ordered proteins in allostery. Here, we propose a comprehensive ensemble model which includes both ordered and disordered states of a two-domain protein, and investigate the role of various state combinations in allosteric effect. By sampling the parameter space, we conclude that disordered proteins are less competitive than ordered proteins in performing allostery from a thermodynamic point of view. The prevalence of IDPs in allosteric regulation is likely determined by all their advantage, but not only by their capacity in endowing allostery.