title: A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
abstract: We present a method which uses DFT (quantum, QM) calculations to improve free energies of binding computed with classical force fields (classical, MM). To overcome the incomplete overlap of configurational spaces between MM and QM, we use a hybrid Monte Carlo approach to generate quickly correct ensembles of structures of intermediate states between a MM and a QM/MM description, hence taking into account a great fraction of the electronic polarization of the quantum system, while being able to use thermodynamic integration to compute the free energy of transition between the MM and QM/MM. Then, we perform a final transition from QM/MM to full QM using a one-step free energy perturbation approach. By using QM/MM as a stepping stone toward the full QM description, we find very small convergence errors (<1 kJ/mol) in the transition to full QM. We apply this method to compute hydration free energies, and we obtain consistent improvements over the MM values for all molecules we used in this study. This approach requires large-scale DFT calculations as the full QM systems involved the ligands and all waters in their simulation cells, so the linear-scaling DFT code ONETEP was used for these calculations.
authors.affiliation: †School of Chemistry, University of Southampton, University Road, Southampton, Hampshire, SO17 1BJ, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Sampson
authors.forename: Thomas
authors.initials: T
authors.lastname: Fox
authors.forename: Christofer S
authors.initials: CS
authors.lastname: Tautermann
authors.affiliation: §School of Chemistry, University of Bristol, Cantocks Close, Bristol, Somerset, BS8 1TS, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Woods
authors.affiliation: †School of Chemistry, University of Southampton, University Road, Southampton, Hampshire, SO17 1BJ, United Kingdom.
authors.forename: Chris-Kriton
authors.initials: CK
authors.lastname: Skylaris
mesh_terms: D003198:Computer Simulation; D004980:Ethane / Q000737:chemistry; D000431:Ethanol / Q000737:chemistry; D019855:Ethylene Glycol / Q000737:chemistry; D008738:Methyl Ethers / Q000737:chemistry; D008956:Models, Chemical; D009010:Monte Carlo Method; D011407:Propane / Q000737:chemistry; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D008738:Methyl Ethers; D012997:Solvents; D014867:Water; D000431:Ethanol; C033413:dimethyl ether; D019855:Ethylene Glycol; D004980:Ethane; D011407:Propane