We describe a novel approach to the calculation of flexibility and mobility in proteins, protein complexes and other large macromolecular complexes like virus capsids. Rather than using conventional molecular dynamics, we use the constraint approach of Lagrange, incorporating covalent bonds, hydrogen bonds, and tethers for hydrophobic interactions. The rigid clusters, including the core, are identified as well as the flexible joints between them. This is used as the basis for dynamics, using Monte Carlo approaches that maintain all the original constraints, as well as van der Waals excluded volumes. The generation a new protein conformation requires about 100 millsecs CPU time on a single processor [1]. These techniques can be used on a single X-ray crystallographic structure to generate an ensemble of structures remarkably similar to those observed in NMR. We also show how this approach can be used to generate multiple protein complexes for use in ligand docking studies. We give examples of the pathways for misfolding proteins, like prions, and also the swelling of viral capsids.
[1] Stephen Wells, Brandon M. Hespenheide, Scott Menor and M.F. Thorpe, to be published by Physical Biology.
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