title: Quantification of Solvent Contribution to the Stability of Noncovalent Complexes.
abstract: We introduce an indirect approach to estimate the solvation contributions to the thermodynamics of noncovalent complex formation through molecular dynamics simulation. This estimation is demonstrated by potential of mean force and entropy calculations on the binding process between β-cyclodextrin (host) and four drug molecules puerarin, daidzin, daidzein, and nabumetone (guest) in explicit water, followed by a stepwise extraction of individual enthalpy (ΔH) and entropy (ΔS) terms from the total free energy. Detailed analysis on the energetics of the host-guest complexation demonstrates that flexibility of the binding partners and solvation-related ΔH and ΔS need to be included explicitly for accurate estimation of the binding thermodynamics. From this, and our previous work on the solvent dependency of binding energies (Zhang et al. J. Phys. Chem. B 2012, 116, 12684-12693), it follows that calculations neglecting host or guest flexibility, or those employing implicit solvent, will not be able to systematically predict binding free energies. The approach presented here can be readily adopted for obtaining a deeper understanding of the mechanisms governing noncovalent associations in solution.
authors.affiliation: Beijing Key Laboratory of Bioprocess, Department of Biochemical Engineering, Beijing University of Chemical Technology , Box 53, 100029 Beijing, China.|Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , Husargatan 3, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Bioprocess, Department of Biochemical Engineering, Beijing University of Chemical Technology , Box 53, 100029 Beijing, China.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Tan
authors.affiliation: Molecular Biophysics Research Group, Hungarian Academy of Sciences , Pázmány sétány 1/C, H-1117 Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Hetényi
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , Husargatan 3, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: van der Spoel