Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery.

ABSTRACT: Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion

SUBMITTER: Fischer M 

PROVIDER: S-EPMC4144196 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature