title: Free-energy differences between states with different conformational ensembles.
abstract: Multiple conformations separated by high-energy barriers represent a challenging problem in free-energy calculations due to the difficulties in achieving adequate sampling. We present an application of thermodynamic integration (TI) in conjunction with the local elevation umbrella sampling (LE/US) method to improve convergence in alchemical free-energy calculations. TI-LE/US was applied to the guanosine triphosphate (GTP) to 8-Br-GTP perturbation, molecules that present high-energy barriers between the anti and syn states and that have inverted preferences for those states. The convergence and reliability of TI-LE/US was assessed by comparing with previous results using the enhanced-sampling one-step perturbation (OSP) method. A linear interpolation of the end-state biasing potentials was sufficient to dramatically improve sampling along the chosen reaction coordinate. Conformational free-energy differences were also computed for the syn and anti states and compared to experimental and theoretical results. Additionally, a coupled OSP with LE/US was carried out, allowing the calculation of conformational and alchemical free energies of GTP and 8-substituted GTP analogs.
authors.affiliation: Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Garate
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
mesh_terms: D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: C060908:8-bromoguanosine triphosphate; D006160:Guanosine Triphosphate