  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.
