Generation of a flexible loop structural ensemble and its application to induced-fit structural changes following ligand binding

Molecular recognition is often mediated by flexible loops that have widely fluctuating structures and are sometimes disordered, but that form particular complex structures following ligand binding. In fact, many loop structures found in the PDB database are too flexible to be determined precisely. A new loop modeling method was therefore developed using force-biased multicanonical molecular dynamics with the implicit solvent model to generate an ensemble of putative loop structures with low free energy values. The method was then used to create ensembles for several flexible loops that were compared with the corresponding NMR and X-ray structures. The induced-fit structural change of dihydrofolate reductase (DHFR) was also predicted from a structural ensemble of ligand-free M20 loop conformations and successive docking simulations.