Atomically detailed simulations of a biomolecular process can provide significant insight to mechanisms and function, and are therefore widely used. Nevertheless, enthusiasm for these simulations is somewhat reduced when we consider their time scale limitation. Time scales of Molecular Dynamics (MD) simulations are restricted to a few microseconds, significantly shorter than time scales of many processes in molecular biophysics, such as rapid and slow folding, conformational transitions and activation, and signal transduction. In the previous funding periods we focused on the calculation of approximate trajectories that describe long time (even millisecond) processes. The trajectories compared favorably with experiments on structural properties of paths. However, the calculation of kinetic properties proved difficult. Determining rate is important since kinetic of cellular processes describes function;it is also at the core of the timely field of System Biology. We developed a new computational technique, Milestoning, to calculate rates. In the next grant period we plan to advance the new methodology, and to compute the kinetics of myosin recovery stroke and allosteric transition in Scapharca hemoglobin. Our algorithms are implemented in the Molecular Dynamics package MOIL which continues to be freely available at http://cbsu.tc.cornell.edu/software/moil/moil.html
The algorithm developed in the grant will help predict kinetics (and function) of proteins and are likely to give better understanding of proteins and their interactions with other molecules (like drugs).
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