RT Journal Article
SR Electronic
T1 Sensitivity in binding free energies due to protein reorganization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 066621
DO 10.1101/066621
A1 Nathan M. Lim
A1 Lingle Wang
A1 Robert Abel
A1 David L. Mobley
YR 2016
UL http://biorxiv.org/content/early/2016/07/28/066621.abstract
AB Tremendous recent improvements in computer hardware, coupled with advances in sampling techniques and force fields, are now allowing protein-ligand binding free energy calculations to be routinely used to aid pharmaceutical drug discovery projects. However, despite these recent innovations, there are still needs for further improvement in sampling algorithms to more adequately sample protein motion relevant to protein-ligand binding. Here, we report our work identifying and studying such clear and remaining needs in the apolar cavity of T4 Lysozyme L99A. In this study, we model recent experimental results that show the progressive opening of the binding pocket in response to a series of homologous ligands.1 Even while using enhanced sampling techniques, we demonstrate that the predicted relative binding free energies (RBFE) are sensitive to the initial protein conformational state. Particularly, we highlight the importance of sufficient sampling of protein conformational changes and demonstrate how inclusion of three key protein residues in the ‘hot’ region of the FEP/REST simulation improves the sampling and resolves this sensitivity.