Quantification of Solvent Contribution to the Stability of Noncovalent Complexes
2013 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, no 10, 4542-4551 p.Article in journal (Refereed) Published
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 beta-cyclodextrin (host) and four drug molecules puerarin, daidzin, daidzein, and nabumetone (guest) in explicit water, followed by a stepwise extraction of individual enthalpy (Delta H) and entropy (Delta S) 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 Delta H and Delta S 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.
Place, publisher, year, edition, pages
2013. Vol. 9, no 10, 4542-4551 p.
IdentifiersURN: urn:nbn:se:uu:diva-212418DOI: 10.1021/ct400404qISI: 000326355100026OAI: oai:DiVA.org:uu-212418DiVA: diva2:677885