Recent Developments of the Molecular Dynamics Flexible Fitting Method

Abstract

Molecular Dynamics Flexible Fitting (MDFF) is a computational method that combines structural information from X-ray crystallography and cryo-electron microscopy (cryo-EM). Cryo-EM provides structural data on biomolecules in their functional states but not at atomic resolution, while X-ray crystallography yields atomic-resolution data but for molecules in crystalline form that renders them often non-functional. MDFF employs molecular dynamics (MD) simulations to bridge the two sets of data, by adding an attractive potential derived from cryo-EM maps to the MD force field, driving atoms toward high-density regions while maintaining a stereochemically correct conformation of the molecules. MDFF has already been successfully applied to study several macromolecular complexes such as the ribosome.To further advance MDFF, we have created a test set consisting of different types of biomolecules in different conformational states. Using this test set, MDFF has been optimized for different types of molecules and conformational changes, providing a useful guideline for users applying MDFF to different biological systems. Moreover, helical symmetry restraints have been incorporated into MDFF as many biological systems studied by MDFF have helical symmetry, such as the family of microbial nitrilases. Information about helical symmetry can now be included in MDFF, improving the quality of the fit on these kinds of systems.