A Quantitative Study of the Effects of Guest Flexibility on Binding Inside a Coordination Cage Host. Issue 1 (23rd November 2016)

• Record Type: Journal Article
• Authors: Taylor, Christopher G. P.; Cullen, William; Collier, Olivia M.; Ward, Michael D.
• Is Part Of: Chemistry. Volume 23:Issue 1(2017)
• Page Start: 206
• Page End: 213
• Publication Date: 2016-11-23
• Subjects: binding constants -- coordination cage -- host–guest chemistry -- self-assembly -- virtual screen; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201604796
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: We have performed a systematic investigation of the effects of guest flexibility on their ability to bind in the cavity of a coordination cage host in water, using two sets of isomeric aliphatic ketones that differ only in the branching patterns of their alkyl chains. Apart from the expected increase in binding strength for C9 over C7 ketones associated with their greater hydrophobic surface area, within each isomeric set there is a clear inverse correlation between binding free energy and guest flexibility, associated with loss of conformational entropy. This can be parameterized by the number of rotatable C−C bonds in the guest, with each additional rotatable bond resulting in a penalty of around 2 kJ mol −1 in the binding free energy, in good agreement with values obtained from protein/ligand binding studies. We used the binding data for the new flexible guests to improve the scoring function that we had previously developed that allowed us to predict binding constants of relatively rigid guests in the cage cavity using the molecular docking programme GOLD (Genetic Optimisation of Ligand Docking). This improved scoring function resulted in a significant improvement in the ability of GOLD to predict binding constants for flexible guests, without any detriment to its ability to predict binding for more rigid guests. Abstract : Ketones in a cage : Using two series of isomeric ketones with different degrees of alkyl substitution as guests, the effects of guest flexibility on binding affinity in the cavity of a synthetic host have been evaluated quantitatively, allowing improved in silico prediction of binding affinities.