title: Resolving the problem of trapped water in binding cavities: prediction of host-guest binding free energies in the SAMPL5 challenge by funnel metadynamics.
abstract: The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host-guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.
authors: Division of Biophysical Chemistry, Chemical Center, Lund University, P.O.B. 124, 22100, Lund, Sweden.
authors: Soumendranath
authors: S
authors: Bhakat
authors: Division of Biophysical Chemistry, Chemical Center, Lund University, P.O.B. 124, 22100, Lund, Sweden. par.soderhjelm@bpc.lu.se.
authors: Pär
authors: 0000-0001-6938-7803
authors: P
authors: Söderhjelm
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012984:Software; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins; D012997:Solvents; D014867:Water
keywords: Binding free energy; Host–guest complex; MD simulation; Metadynamics; SAMPL5