Energy penalties enhance flexible receptor docking in a model cavity
Anna S. Kamenik, Isha Singh, Parnian Lak, Trent E. Balius, Klaus R. Liedl, Brian K. Shoichet
Abstract
Significance The dynamic nature of biomolecules is typically neglected in docking screens for ligand discovery. The key to benefitting from various receptor conformations is not only structural but also thermodynamic information. Here, we test a general approach that uses conformational preferences from enhanced and conventional molecular dynamics simulations to account for the cost of transitions to high-energy states. Including this information as a conformational penalty term in a docking, scoring function, we perform retrospective and prospective screens and experimentally confirm predicted ligands with T m upshift and X-ray crystallography. This not only allows us to test the predicted ligands for binding, it also tests whether they bind to the conformation of the binding site for which they were predicted.