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A statistical approach to the interpretation of molecular dynamics simulations of calmodulin equilibrium dynamics

Vladimir A. Liki², Paul R. Gooley^1,2, Terence P. Speed^3,4 and Emanuel E. Strehler⁵

¹ Department of Biochemistry and Molecular Biology, ² Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia
³ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
⁴ Department of Statistics, University of California, Berkeley, California 94720-3860, USA
⁵ Department of Biochemistry, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA

(RECEIVED June 30, 2005; FINAL REVISION September 18, 2005; ACCEPTED September 24, 2005)

A sample of 35 independent molecular dynamics (MD) simulations of calmodulin (CaM) equilibrium dynamics was prepared from different but equally plausible initial conditions (20 simulations of the wild-type protein and 15 simulations of the D129N mutant). CaM’s radius of gyration and backbone mean-square fluctuations were analyzed for the effect of the D129N mutation, and simulations were compared with experiments. Statistical tests were employed for quantitative comparisons at the desired error level. The computational model predicted statistically significant compaction of CaM relative to the crystal structure, consistent with the results of small-angle X-ray scattering (SAXS) experiments. This effect was not observed in several previously reported studies of (Ca²⁺)₄-CaM, which relied on a single MD run. In contrast to radius of gyration, backbone mean-square fluctuations showed a distinctly non-normal and positively skewed distribution for nearly all residues. Furthermore, the D129N mutation affected the backbone dynamics in a complex manner and reduced the mobility of Glu123, Met124, Ile125, Arg126, and Glu127 located in the adjacent -helix G. The implications of these observations for the comparisons of MD simulations with experiments are discussed. The proposed approach may be useful in studies of protein equilibrium dynamics where MD simulations fall short of properly sampling the conformational space, and when the comparison with experiments is affected by the reproducibility of the computational model.

Keywords: MD simulations; protein dynamics; precision; reproducibility; accuracy; calmodulin

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051681605.

Reprints requests to: Dr Vladimir A. Liki, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia; e-mail: vlikic{at}unimelb.edu.au; fax: 61-3-9347-4079.

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