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Dynamics of Ca²⁺-saturated calmodulin D129N mutant studied by multiple molecular dynamics simulations

Vladimir A. Liki¹, Emanuel E. Strehler² and Paul R. Gooley¹

¹ Department of Biochemistry and Molecular Biology, Russell Grimwade School of Biochemistry, The University of Melbourne, Parkville, VIC 3052, Australia
² Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA

Reprint requests to: Vladimir A. Liki, Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC 3052, Australia; e-mail: vlikic{at}unimelb.edu.au; fax: 61-3-9347 7730.

Fifteen independent 1-nsec MD simulations of fully solvated Ca²⁺ 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 Ca²⁺ ions remained in their binding sites, and retained a single water ligand as observed in the crystal structure. The coordination of Ca²⁺ 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 Ca²⁺ coordination was observed. The Ca²⁺ binding loop in EF-hand II was observed to dynamically sample conformations related to the Ca²⁺-free form. Repeated MD simulations implicate two well-defined conformations of Ca²⁺ binding loop II, whereas similar effect was not observed for loops I, III, and IV. In 8 out of 15 MD simulations Ca²⁺ binding loop II adopted an alternative conformation in which the Thr62 C=O group was displaced from the Ca²⁺ coordination by a water molecule, resulting in the Ca²⁺ ion ligated by two water molecules. The alternative conformation of the Ca²⁺ 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.

Keywords: Calmodulin; CaM; dynamics; EF-hands; Ca²⁺ binding; multiple MD simulations

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This article has been cited by other articles:

				V. A. Likic, P. R. Gooley, T. P. Speed, and E. E. Strehler A statistical approach to the interpretation of molecular dynamics simulations of calmodulin equilibrium dynamics Protein Sci., December 1, 2005; 14(12): 2955 - 2963. [Abstract] [Full Text] [PDF]