Forging tools for refining predicted protein structures

Significance Structural biology would benefit greatly from having a purely computational means of obtaining protein structural models that rival in accuracy those based on X-ray diffraction experiments. Intermediate resolution structures, with accuracies that are a few angstroms above the experimental uncertainty assigned to X-ray structures, can now be routinely generated. Here, we draw inspiration from blacksmithing to help us devise methods that can refine intermediate resolution models to within experimental accuracy using only modest computational resources. Like the blacksmiths, we use mechanical deformations along collective modes to encourage equilibration. We find that refinement is impeded by slow rotations of bulky side chains in the protein interior and that lowering these barriers while sampling along deformation modes further helps to refine predicted structures.