Molecular Dynamics Study of Conformations of Beta-Cyclodextrin and its Eight Derivatives in Four Different Solvents

TL;DR

This study uses molecular dynamics simulations to analyze how different solvents affect the structure of beta-cyclodextrin and its derivatives, revealing solvent-dependent stability and potential drug delivery applications.

Contribution

It provides detailed insights into solvent effects on beta-cyclodextrin derivatives' conformations, highlighting the unique stability of 2,6-ETβCD across solvents.

Findings

Hydrophobic 2,6-ETβCD maintains stable cavity in all solvents.

Polar solvents cause significant structural deformation in most βCD derivatives.

Hydrogen bonding with solvents influences structural stability.

Abstract

Understanding the atomic level interactions and the resulting structural characteristics is required for developing beta-cyclodextrin ($\beta$CD) derivatives for pharmaceutical and other applications. The effect of four different solvents on the structures of the native $\beta$CD and its hydrophilic (methylated $\beta$CD; ME$\beta$CD and hydroxypropyl $\beta$CD; HP$\beta$CD) and hydrophobic derivatives (ethylated $\beta$CD; ET$\beta$CD) were explored using molecular dynamics (MD) simulations and solvation free energy calculations. The native $\beta$CD, 2-ME$\beta$CD, 6-ME$\beta$CD, 2,6-DM$\beta$CD, 2,3,6-TM$\beta$CD, 6-HP$\beta$CD, 2,6-HP$\beta$CD and 2,6-ET$\beta$CD in non-polar solvents (cyclohexane; CHX and octane; OCT) were stably formed in symmetric cyclic cavity shape through their intramolecular hydrogen bonds. In contrast, $\beta$CDs in polar solvents (methanol; MeOH and water; WAT) exhibited large structural changes and fluctuations leading to significant deformations of their cavities. Hydrogen bonding with polar solvents was found to be one of the major contributors to this behavior: solvent-\b{eta}CD hydrogen bonding strongly competes with intramolecular bonding leading to significant changes in structural stability of $\beta$CDs. The exception to this is the hydrophobic 2,6-ET$\beta$CD which retained its spherical cavity in all solvents. Based on this, it is proposed that 2,6-ET$\beta$CD can act as a sustained release drug carrier.