title: Absolute binding free energies for octa-acids and guests in SAMPL5 : Evaluating binding free energies for octa-acid and guest complexes in the SAMPL5 blind challenge.
abstract: As part of the SAMPL5 blind prediction challenge, we calculate the absolute binding free energies of six guest molecules to an octa-acid (OAH) and to a methylated octa-acid (OAMe). We use the double decoupling method via thermodynamic integration (TI) or Hamiltonian replica exchange in connection with the Bennett acceptance ratio (HREM-BAR). We produce the binding poses either through manual docking or by using GalaxyDock-HG, a docking software developed specifically for this study. The root mean square deviations for our most accurate predictions are 1.4 kcal mol-1for OAH with TI and 1.9 kcal mol-1for OAMe with HREM-BAR. Our best results for OAMe were obtained for systems with ionic concentrations corresponding to the ionic strength of the experimental solution. The most problematic system contains a halogenated guest. Our attempt to model the σ-hole of the bromine using a constrained off-site point charge, does not improve results. We use results from molecular dynamics simulations to argue that the distinct binding affinities of this guest to OAH and OAMe are due to a difference in the flexibility of the host. We believe that the results of this extensive analysis of host-guest complexes will help improve the protocol used in predicting binding affinities for larger systems, such as protein-substrate compounds.
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung, and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA. florentina.tofoleanu@nih.gov.
authors.forename: Florentina
authors.identifier: 0000-0002-2236-0512
authors.initials: F
authors.lastname: Tofoleanu
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung, and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Juyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung, and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Pickard Iv
authors.affiliation: Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: König
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung, and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.|Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Baek
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Chaok
authors.initials: C
authors.lastname: Seok
authors.affiliation: Laboratory of Computational Biology, National Institutes of Health - National Heart, Lung, and Blood Institute, 5635 Fishers Lane, T-900 Suite, Rockville, MD, 20852, USA.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Brooks
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D012984:Software; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins; D012997:Solvents
keywords: Bennett acceptance ratio; Binding free energy simulations; Double decoupling method; GalaxyDock-HG; Hamiltonian replica exchange; Molecular dynamics simulations; Thermodynamic integration