title: Separated topologies--a method for relative binding free energy calculations using orientational restraints.
abstract: Orientational restraints can improve the efficiency of alchemical free energy calculations, but they are not typically applied in relative binding calculations, which compute the affinity difference been two ligands. Here, we describe a new "separated topologies" method, which computes relative binding free energies using orientational restraints and which has several advantages over existing methods. While standard approaches maintain the initial and final ligand in a shared orientation, the separated topologies approach allows the initial and final ligands to have distinct orientations. This avoids a slowly converging reorientation step in the calculation. The separated topologies approach can also be applied to determine the relative free energies of multiple orientations of the same ligand. We illustrate the approach by calculating the relative binding free energies of two compounds to an engineered site in Cytochrome C Peroxidase.
authors: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th St., San Francisco, California 94143-2550, USA. grocklin@gmail.com
authors: Gabriel J
authors: GJ
authors: Rocklin
authors: David L
authors: DL
authors: Mobley
authors: Ken A
authors: KA
authors: Dill
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D003578:Cytochrome-c Peroxidase / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013816:Thermodynamics
chemical_list: C522780:4-azaindole; D001562:Benzimidazoles; D007211:Indoles; C031000:benzimidazole; D003578:Cytochrome-c Peroxidase