Generalized Born and Explicit Solvent Models for Free Energy Calculations in Organic Solvents: Cyclodextrin Dimerization
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- 作者：Haiyang Zhang ; Tianwei Tan ; David van der Spoel
- 刊名：Journal of Chemical Theory and Computation
- 出版年：2015
- 出版时间：November 10, 2015
- 年：2015
- 卷：11
- 期：11
- 页码：5103-5113
- 全文大小：672K
- ISSN：1549-9626
文摘
Evaluation of solvation (binding) free energies with implicit solvent models in different dielectric environments for biological simulations as well as high throughput ligand screening remain challenging endeavors. In order to address how well implicit solvent models approximate explicit ones we examined four generalized Born models (GBStill, GBHCT, GBOBCI, and GBOBCII) for determining the dimerization free energy (螖G0) of 尾-cyclodextrin monomers in 17 implicit solvents with dielectric constants (D) ranging from 5 to 80 and compared the results to previous free energy calculations with explicit solvents (Zhang et al. J. Phys. Chem. B 2012, 116, 12684鈭?2693). The comparison indicates that neglecting the environmental dependence of Born radii appears acceptable for such calculations involving cyclodextrin and that the GBStill and GBOBCI models yield a reasonable estimation of 螖G0, although the details of binding are quite different from explicit solvents. Large discrepancies between implicit and explicit solvent models occur in high-dielectric media with strong hydrogen bond (HB) interruption properties. 螖G0 with the GB models is shown to correlate strongly to 2(D鈥?)/(2D+1) (R2 鈭?0.90) in line with the Onsager reaction field (Onsager J. Am. Chem. Soc. 1936, 58, 1486鈭?493) but to be very sensitive to D (D < 10) as well. Both high-dielectric environments where hydrogen bonds are of interest and low-dielectric media such as protein binding pockets and membrane interiors therefore need to be considered with caution in GB-based calculations. Finally, a literature analysis of Gibbs energy of solvation of small molecules in organic liquids shows that the Onsager relation does not hold for real molecules since the correlation between 螖G0 and 2(D鈥?)/(2D+1) is low for most solutes. Interestingly, explicit solvent calculations of the solvation free energy (Zhang et al. J. Chem. Inf. Model. 2015, 55, 1192鈭?201) reproduce the weak experimental correlations with 2(D鈥?)/(2D+1) very well.