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Dynamics of Ca2+-saturated calmodulin D129N mutant studied by multiple molecular dynamics simulations
Vladimir A Likić1, Emanuel E Strehler, Paul R Gooley
1Department of Biochemistry and Molecular Biology, Russell Grimwade School of Biochemistry, The University of Melbourne, Parkville, VIC 3052, Australia. vlikic@unimelb.edu.au
Protein Science : a Publication of the Protein Society
|September 23, 2003
Summary
Mutant calmodulin (CaM) simulations reveal Ca(2+) ions remain bound. Loop II in Ca(2+)-binding EF-hand IV shows dynamic sampling of alternative conformations, suggesting preformed states for microsecond exchange.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biophysics
Background:
- Calmodulin (CaM) is a crucial calcium-binding protein involved in cellular signaling.
- Mutations in CaM can alter its calcium-binding properties and downstream functions.
- Understanding CaM dynamics is key to elucidating its regulatory mechanisms.
Purpose of the Study:
- To investigate the dynamic properties of a Ca(2+)-saturated calmodulin (CaM) mutant D129N using molecular dynamics (MD) simulations.
- To analyze the Ca(2+) ion coordination and binding loop conformations in the mutant CaM.
- To explore the relationship between nanosecond-scale dynamics and potential microsecond conformational exchange.
Main Methods:
- Performed fifteen independent 1-nanosecond (nsec) MD simulations of fully solvated Ca(2+)-saturated CaM mutant D129N.
- Analyzed Ca(2+) ion coordination states and water ligand interactions.
- Examined the conformational landscape of Ca(2+) binding loops, particularly in EF-hand II.
Main Results:
- All four Ca(2+) ions remained bound in their respective sites throughout the simulations.
- EF-hands I, II, and III exhibited sevenfold Ca(2+) coordination, while EF-hand IV showed an anomalous eightfold coordination due to the D129N mutation.
- Ca(2+) binding loop II dynamically sampled conformations related to the Ca(2+)-free state, with two distinct conformations observed, one involving water displacement in 8/15 simulations.
Conclusions:
- The D129N mutation perturbs Ca(2+) coordination in EF-hand IV but maintains overall Ca(2+) ion saturation.
- Ca(2+) binding loop II exhibits significant conformational flexibility, adopting an alternative conformation linked to "closed" states observed previously.
- MD simulations suggest that conformational states involved in microsecond exchange are partially preformed on the nanosecond timescale.