Cyclodextrin (CD), a cyclic oligosaccharide of α-D-glucose, is a popular drug carrier that can encapsulate drug molecules within its cavity. Although CD crystal structures have been known for a century, their conformational dynamics in solution and the molecular details of CD-solvent interactions remain unexplored. With the recent development to carbohydrate specific molecular force fields, we examined their capability to capture the structural and hydration properties of native CDs in comparison with the available experimental data. We developed a simple and novel technique to identify the water molecules within the cavity which resembles a conical hourglass. We found the cavity water molecules to be energetically frustrated, explaining the earlier hypothesis of energy driven CD-guest complexation, in contrast to the typical entropically driven hydrophobic association. Further, we explored the influence of common substitutions like methyl and 2-hydroxypropyl that are known to enhance the aqueous solubility of CD. Our study reveals that due to favorable CD-solvent interactions, the glucose units get tilted more leading to structural distortion and closure of the cavity. Upon encapsulation of the guest the tilting of glucose units gets arrested and the cavity structure remains open. Lastly, we discuss the necessity to verify the mode of drug binding and the extent of drug encapsulation into the CD cavity to obtain accurate free energy estimates through MM-PBSA analysis

Publications:

REFEREED JOURNALS BASED ON THESIS
1. Avilasha A. Sandilya, Upendra Natarajan, and M. Hamsa Priya; Molecular View into the Cyclodextrin Cavity: Structure and Hydration; ACS Omega 2020, 5, 40, 25655–25667

REFEREED JOURNALS (OTHERS)
1. Smrithi Sundar, Avilasha A. Sandilya and M. Hamsa Priya; Unraveling the Influence of Osmolytes on Water Hydrogen-Bond Network: From Local Structure to Graph Theory Analysis; J Chem Inf Model 2021, 61(8), 3927-3944