Comparing allosteric transitions in the domains of calmodulin through coarse-grained simulations

TL;DR

This study uses coarse-grained simulations to compare the allosteric transition mechanisms of calmodulin's two domains, revealing differences in unfolding behavior and stability that affect calcium binding dynamics.

Contribution

It provides the first detailed simulation-based comparison of calmodulin domains, highlighting the role of unfolding in their allosteric transitions.

Findings

nCaM follows a two-state transition mechanism.

cCaM involves unfolding and refolding during transitions.

Unfolded state population is higher in cCaM at physiological conditions.

Abstract

Calmodulin (CaM) is a ubiquitous calcium binding protein consisting of two structurally similar domains with distinct stabilities, binding affinities, and flexibilities. We present coarse grained simulations that suggest the mechanism for the domain's allosteric transitions between the open and closed conformations depend on subtle differences in the folded state topology of the two domains. Throughout a wide temperature range, the simulated transition mechanism of the N-terminal domain (nCaM) follows a two-state transition mechanism while domain opening in the C-terminal domain (cCaM) involves unfolding and refolding of the tertiary structure. The appearance of the unfolded intermediate occurs at a higher temperature in nCaM than it does in cCaM consistent with nCaM's higher thermal stability. Under approximate physiological conditions, the simulated unfolded state population of cCaM accounts for 10% of the population with nearly all of the sampled transitions (approximately 95%) unfolding and refolding during the conformational change. Transient unfolding significantly slows the domain opening and closing rates of cCaM. This potentially influences the mechanism of calcium binding to each domain.