The influence of intrinsic folding mechanism of an unfolded protein on the coupled folding‐binding process during target recognition

Abstract

Intrinsically disordered proteins (IDPs) are extensively involved in dynamic signaling processes which require a high association rate and a high dissociation rate for rapid binding/unbinding events and at the same time a sufficient high affinity for specific recognition. Although the coupled folding‐binding processes of IDPs have been extensively studied, it is still impossible to predict whether an unfolded protein is suitable for molecular signaling via coupled folding‐binding. In this work, we studied the interplay between intrinsic folding mechanisms and coupled folding‐binding process for unfolded proteins through molecular dynamics simulations. We first studied the folding process of three representative IDPs with different folded structures, that is, c‐Myb, AF9, and E3 rRNase. We found the folding free energy landscapes of IDPs are downhill or show low barriers. To further study the influence of intrinsic folding mechanism on the binding process, we modulated the folding mechanism of barnase via circular permutation and simulated the coupled folding‐binding process between unfolded barnase permutant and folded barstar. Although folding of barnase was coupled to target binding, the binding kinetics was significantly affected by the intrinsic folding free energy barrier, where reducing the folding free energy barrier enhances binding rate up to two orders of magnitude. This accelerating effect is different from previous results which reflect the effect of structure flexibility on binding kinetics. Our results suggest that coupling the folding of an unfolded protein with no/low folding free energy barrier with its target binding may provide a way to achieve high specificity and rapid binding/unbinding kinetics simultaneously.

Molecular dynamics simulations revealed topological frustration in the binding-wrapping process of eIF4G with eIF4E

“…30 Topology-based coarse-grained model of eIF4G/eIF4E complex In this work, we investigated the coupled folding-binding process of eIF4G with eIF4E using molecular dynamics (MD) simulations using a topology-based coarse-grained model. [31][32][33][34][35] In this model, each residue is represented by a bead located at the Ca atom and the interaction potential is described by the following equation:…”

Recent development of atomistic force fields and simulations of intrinsically disordered proteins

“…MD能够对实验进行补充, 在原子水平上模 拟IDPs和生物大分子的结合, 对结合中间体和关键残 基进行细致的描述 [83] . 之前对IDPs结合的研究常常使 用粗粒化力场 [84,85] 或者隐式溶剂模型 [86] 来提高计算效 率, 但是这会牺牲一定的准确性. 随着图形处理器(graphics processing unit, GPU) [87] 和新的增强抽样方法的 出现 [88~90] , 越来越多的研究使用全原子力场搭配显式 溶剂模型研究IDPs的结合过程(表2).…”