title: Non-Boltzmann thermodynamic integration (NBTI) for macromolecular systems: relative free energy of binding of trypsin to benzamidine and benzylamine.
abstract: The relative free energies of binding of trypsin to two amine inhibitors, benzamidine (BZD) and benzylamine (BZA), were calculated using non-Boltzmann thermodynamic integration (NBTI). Comparison of the simulations with the crystal structures of both complexes, trypsin-BZD and trypsin-BZA, shows that NBTI simulations better sample conformational space relative to thermodynamic integration (TI) simulations. The relative binding free energy calculated using NBTI was much closer to the experimentally determined value than that obtained using TI. The error in the TI simulation was found to be primarily due to incorrect sampling of BZA's conformation in the binding pocket. In contrast, NBTI produces a smooth mutation from BZD to BZA using a surrogate potential, resulting in a much closer agreement between the inhibitors' conformations and the omit electron density maps. This superior agreement between experiment and simulation, of both relative binding free energy differences and conformational sampling, demonstrates NBTI's usefulness for free energy calculations in macromolecular simulations.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ota
authors.forename: C
authors.initials: C
authors.lastname: Stroupe
authors.forename: J M
authors.initials: JM
authors.lastname: Ferreira-da-Silva
authors.forename: S A
authors.initials: SA
authors.lastname: Shah
authors.forename: M
authors.initials: M
authors.lastname: Mares-Guia
authors.forename: A T
authors.initials: AT
authors.lastname: Brunger
mesh_terms: D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D007700:Kinetics; D046911:Macromolecular Substances; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055672:Static Electricity; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D001550:Benzamidines; D001596:Benzylamines; D046911:Macromolecular Substances; D014361:Trypsin Inhibitors; C030796:benzylamine; D014357:Trypsin; C032157:benzamidine