An Approximate Method in Using Molecular Mechanics Simulations To Study Slow Protein Conformational Changes

The broad range of characteristic motions in proteins has limited the applicability of molecular dynamics simulations in studying large-scale conformational transitions. We present an approximate method, making use of standard MD simulations and using a much larger integration time step, to obtain the structural changes for slow systematic motions of large complex systems. We show the applicability of this method by simulating the open to closed Calmodulin calcium binding domain conformational changes. Starting with the Ca2+-bound X-ray structure, and after the removal of the Ca2+ ions, our calculation yielded intermediate conformations during the rearrangement of helices in each Ca2+ binding pocket, leading to a structure with a lowest rmsd of 1.56 Å compared to the NMR apo-calmodulin structure.