Coarse-grained molecular simulations of allosteric cooperativity

摘要

Interactions between a protein and a ligand are often accompanied by aredistribution of the population of thermally accessible conformations. Thisdynamic response of the protein's functional energy landscape enables a proteinto modulate binding affinities and control binding sensitivity to ligandconcentration. In this paper, we investigate the structural origins of bindingaffinity and allosteric cooperativity of binding two calcium ions to eachdomain of calmodulin (CaM) through simulations of a simple coarse-grainedmodel. In this model, the protein's conformational transitions between open andclosed conformational ensembles are simulated explicitly and ligand binding andunbinding is treated implicitly within the Grand Canonical Ensemble. Ligandbinding is cooperative because the binding sites are coupled through a shift inthe dominant conformational ensemble upon binding. The classicMonod-Wyman-Changeux model of allostery with appropriate binding free energy tothe open and closed ensembles accurately describes the simulated bindingthermodynamics. The simulations predict that the two domains of CaM havedistinct binding affinity and cooperativity. In particular, C-terminal domainbinds calcium with higher affinity and greater cooperativity than theN-terminal domain. From a structural point of view, the affinity of anindividual binding loop depends sensitively on the loop's structuralcompatibility with the ligand in the bound ensemble, as well as theconformational flexibility of the binding site in the unbound ensemble.