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 . That is, we find that cCaM unfolds more readily along the transition route than nCaM. Furthermore, unfolding and refolding of the domain significantly slows the domain opening and closing rates of cCaM , a distinct scenario which can potentially influence the mechanism of calcium binding to each domain.
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.
R
. That is, we find that cCaM unfolds more readily along the transition route than nCaM. Furthermore,
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\%)
R
of the domain
during the conformational change. Transient unfolding
R
, a distinct scenario which can potentially influence
. This potentially influences