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Dynamics of Ca 2+ ‐saturated calmodulin D129N mutant studied by multiple molecular dynamics simulations
Author(s) -
Likić Vladimir A.,
Strehler Emanuel E.,
Gooley Paul R.
Publication year - 2003
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.0377803
Subject(s) - calmodulin , molecular dynamics , chemistry , microsecond , crystallography , molecule , ion , ef hand , mutant , stereochemistry , calcium , computational chemistry , physics , biochemistry , organic chemistry , astronomy , gene
Fifteen independent 1‐nsec MD simulations of fully solvated Ca 2+ saturated calmodulin (CaM) mutant D129N were performed from different initial conditions to provide a sufficient statistical basis to gauge the significance of observed dynamical properties. In all MD simulations the four Ca 2+ ions remained in their binding sites, and retained a single water ligand as observed in the crystal structure. The coordination of Ca 2+ ions in EF‐hands I, II, and III was sevenfold. In EF‐hand IV, which was perturbed by the mutation of a highly conserved Asp129, an anomalous eightfold Ca 2+ coordination was observed. The Ca 2+ binding loop in EF‐hand II was observed to dynamically sample conformations related to the Ca 2+ ‐free form. Repeated MD simulations implicate two well‐defined conformations of Ca 2+ binding loop II, whereas similar effect was not observed for loops I, III, and IV. In 8 out of 15 MD simulations Ca 2+ binding loop II adopted an alternative conformation in which the Thr62 〉C=O group was displaced from the Ca 2+ coordination by a water molecule, resulting in the Ca 2+ ion ligated by two water molecules. The alternative conformation of the Ca 2+ binding loop II appears related to the “closed” state involved in conformational exchange previously detected by NMR in the N‐terminal domain fragment of CaM and the C‐terminal domain fragment of the mutant E140Q. MD simulations suggest that conformations involved in microsecond exchange exist partially preformed on the nanosecond time scale.