Inherent flexibility and protein function: the open/closed conformational transition of the N-terminal domain of calmodulin

Abstract

The key to understanding a protein's function often lies in its conformational dynamics. We develop a coarse-grained variational model to investigate the interplay between structural transitions, conformational flexibility and function of N-terminal calmodulin (nCaM) domain. In this model, two energy basins corresponding to the ``closed'' apo conformation and ``open'' holo conformation of nCaM domain are connected by a uniform interpolation parameter. The resulting detailed transition route from our model is largely consistent with the recently proposed EF$\beta$-scaffold mechanism in EF-hand family proteins. We find that the N-terminal part in calcium binding loops I and II shows higher flexibility than the C-terminal part which form this EF$\beta$-scaffold structure. The structural transition of binding loops I and II are compared in detail. Our model predicts that binding loop II, with higher flexibility and early structural change than binding loop I, dominates the conformational transition in nCaM domain.