Affinity and Putative Entrance Mechanisms of Alkyl Sulfates into the Β-Cd Cavity

Cyclodextrins (CDs) are novel pharmaceutical excipients and are widely used in the pharmaceutical industry and drug delivery due to their ability to form host-guest complexes. There are countless structural features of guest molecules responsible for the efficiency of guest-CD interactions. Among these factors, the hydrophobic moieties of a guest and their size are commonly considered to govern its binding affinity to CD molecules. Experimentally, it is often challenging to extract structural and dynamic information at the atomic scale about CD inclusion complexes, especially in the aqueous phase. Therefore, this study consisted of experimental (isothermal titration calorimetry and conductometric titration) and in silico analysis to rigorously characterize the interactions of beta-CD with three alkyl sulfates of different hydrophobic chain lengths: sodium dodecyl sulfate (S12S), sodium decyl sulfate (S10S) and sodium decyl sulfate (S8S) in aqueous solutions. We find that the hydrophobic interactions are not always a key factor leading to the formation of stable inclusion complexes. Our results demonstrate that van der Waals interactions contribute more to complexation efficiency for sulfates with a longer hydrophobic tail, whereas electrostatic interactions are more pronounced for sulfates with shorter ones. Furthermore, we propose and discuss for the first time the putative mechanisms of the guest entering the host cavity conditioned by the lengths of hydrocarbon chains of alkyl sulfates. Finally, we prove that different types of inclusion complexes can exist in a conformational equilibrium depending on the size of a guest tail. (C) 2022 Elsevier B.V. All rights reserved.