Abstract
To characterize the dynamic behavior of calmodulin in solution, we
have carried out molecular dynamics (MD) simulations of the Ca$^2+$-loaded
structure. The crystal structure of calmodulin was placed in a solvent
sphere of radius 44 A, and 6 Cl$^-$ and 22 Na$^+$ ions were
included to neutralize the system and to model a 150 mM salt concentration.
The total number of atoms was 32,867. During the 3-ns simulation,
the structure exhibits large conformational changes on the nanosecond
time scale. The central alpha-helix, which has been shown to unwind
locally upon binding of calmodulin to target proteins, bends and
unwinds near residue Arg74. We interpret this result as a preparative
step in the more extensive structural transition observed in the
"flexible linker" region 74-82 of the central helix upon complex
formation. The major structural change is a reorientation of the
two Ca$^2+$-binding domains with respect to each other and a
rearrangement of alpha-helices in the N-terminus domain that makes
the hydrophobic target peptide binding site more accessible. This
structural rearrangement brings the domains to a more favorable position
for target binding, poised to achieve the orientation observed in
the complex of calmodulin with myosin light-chain kinase. Analysis
of solvent structure reveals an inhomogeneity in the mobility of
water in the vicinity of the protein, which is attributable to the
hydrophobic effect exerted by calmodulin's binding sites for target
peptides.
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