Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

Authors

  • Leo S. D. Caves,

    1. Department of Chemistry and Clinical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138
    2. Department of Chemistry, University of York, York, YOl 5DD, United Kingdom
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  • Jeffrey D. Evanseck,

    1. Department of Chemistry and Clinical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138
    Current affiliation:
    1. Department of Chemistry, University of Miami, P.O. Box 249118, Green Gables, Florida 33124
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  • Martin Karplus

    Corresponding author
    1. Department of Chemistry and Clinical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138
    2. Laboratoire de Chimie Biophysique, Université ISIS, Louis Pasteur, 4 Rue Blaise Pascal, 67000 Strasbourg, France
    • Laboratoire de ChimieBiophy-sique, Institut le Bel, Universite Pasteur, 4 Rue Blaise Pascal, 67000 Stras- bourg, France
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Abstract

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

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