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

TL;DR

This study introduces a coarse-grained variational model to analyze the conformational transition of the N-terminal calmodulin domain, revealing the dominant role of flexible binding loop II in the open/closed transition.

Contribution

The paper develops a novel variational modeling approach to elucidate the conformational dynamics and transition pathways of nCaM, aligning with experimental mechanisms.

Findings

Binding loop II exhibits higher flexibility and initiates structural change.

The transition pathway aligns with the EFβ-scaffold mechanism.

N-terminal loops are more flexible than C-terminal loops.

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.