title: Sensitivity in Binding Free Energies Due to Protein Reorganization.
abstract: 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, given enough simulation time.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Lim
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.forename: David L
authors.initials: DL
authors.lastname: Mobley
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009113:Muramidase / Q000737:chemistry* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D008024:Ligands; D009113:Muramidase