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We explore how inherent flexibility of a protein molecule influences themechanism controlling the kinetics of allosteric transitions using avariational model inspired from work in protein folding. The strikingdifferences in the predicted transition mechanism for the opening of the twodomains of calmodulin (CaM) emphasizes that inherent flexibility is key tounderstanding the complex conformational changes that occur in proteins. Inparticular, the C-terminal domain of CaM (cCaM) which is inherently lessflexible than its N-terminal domain (nCaM) reveals "cracking" or local partialunfolding during the open/closed transition. This result is in harmony with thepicture that cracking relieves local stresses due to conformationaldeformations of a sufficiently rigid protein. We also compare theconformational transition in a recently studied "even-odd" paired fragment ofCaM. Our results rationalize the different relative binding affinities of theEF-hands in the engineered fragment compared to the intact "odd-even" pairedEF-hands (nCaM and cCaM) in terms of changes in flexibility along thetransition route. Aside from elucidating general theoretical ideas about thecracking mechanism, these studies also emphasize how the remarkable intrinsicplasticity of CaM underlies conformational dynamics essential for its diversefunctions.

Inherent flexibility determines the transition mechanisms of the EF-hands of Calmodulin