The molecular dynamics flexible fitting (MDFF) method can be used to flexibly fit atomic structures into density maps. The method consists of adding external forces proportional to the gradient of the density map into a molecular dynamics (MD) simulation of the atomic structure.  Thus, high-resolution, but conformationally limited structures of individual components from, e.g., X-ray crystallography, can be fitted into cryo-electron microscopy maps of large, physiological complexes. I have utilized MDFF to determine the structures of a number of biologically and industrially relevant complexes, including ribosomes bound to the translocon (see above) and spiral-forming nitrilases. In the process, I have developed additional refinements to the MDFF method, such as incorporating symmetry-based restraints during fitting.  I am also pushing the boundaries of MDFF by applying it to cryo-tomography data, which is typically at a significantly lower resolution than cryo-EM data.

MDFF is currently implemented in the MD package NAMD.  More details can be found on the official MDFF webpage.

Publications