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

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

2008-07-10

arxiv.org/abs/0807.1699v1

Biology

Quantitative Biology

Quantitative Methods

17 pages, 7 figures

Scientific paper

10.1073/pnas.0806872106

We explore how inherent flexibility of a protein molecule influences the mechanism controlling the kinetics of allosteric transitions using a variational model inspired from work in protein folding. The striking differences in the predicted transition mechanism for the opening of the two domains of calmodulin (CaM) emphasizes that inherent flexibility is key to understanding the complex conformational changes that occur in proteins. In particular, the C-terminal domain of CaM (cCaM) which is inherently less flexible than its N-terminal domain (nCaM) reveals "cracking" or local partial unfolding during the open/closed transition. This result is in harmony with the picture that cracking relieves local stresses due to conformational deformations of a sufficiently rigid protein. We also compare the conformational transition in a recently studied "even-odd" paired fragment of CaM. Our results rationalize the different relative binding affinities of the EF-hands in the engineered fragment compared to the intact "odd-even" paired EF-hands (nCaM and cCaM) in terms of changes in flexibility along the transition route. Aside from elucidating general theoretical ideas about the cracking mechanism, these studies also emphasize how the remarkable intrinsic plasticity of CaM underlies conformational dynamics essential for its diverse functions.

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