Conformations of Lower-Size Large Cyclodextrins (DP from 10 to 30) Derived from Conformational Search with Molecular Dynamics and Principal Component Analysis

Petko      Ivanov

Abstract

A new class of compounds, the large-ring cyclodextrins (LR-CDs), attracted attention in recent years, and advances were marked in the study of their physicochemical properties in spite of existing difficulties in their synthesis, isolation and purification. Practical applications were also reported of this new class of compounds. Understanding the mechanism of their action requires knowledge of the macroring conformational dynamics. In view of the difficulties with the experimental examination of the conformations of LR-CDs, computational modeling and simulation methods provide useful tool to gain information about their conformational dynamics, the energetics, and the complex-forming ability. This review summarizes our computational results on the conformations of large-ring cyclodextrins. There are ample evidences to attempt classification (according to their preferred conformation) of the LR-CDs in the range for DP from 10 to 30. Open bend boat-like macrorings are the representative conformations of CD10 to CD13. Two loops situated in mutually perpendicular planes (shaped as number eight) were clearly seen in the average structure of CD14. CD13 and CD14 mark the borderline between lower and higher flexibilities of the CDs macrorings. Two winded single helical strands, apposing each other at different directions, dominate in the structures of the next three LR-CDs (CD15 to CD17), although the CD14-like conformation was also monitored for some of them (CD15, CD17). Two pseudo-cavities with the sizes of α- CD and β-CD were displayed by the average conformations of CD15. These are favorable circumstances for CD14 and CD15 to display better inclusion properties in comparison to the neighbor LR-CDs of higher DP. An expected resemblance with circularized three-turn single helical structure was confirmed for CD21. The CDs from CD22 to CD25 may assume also CD21- and CD26-like conformations during some simulation intervals. Two representative conformations of CD26 (and the CDs in the close vicinity of CD26) are characterized by the presence of two elongated loops with one or two helical turns. A conformation of CD27 resembles the CD21-like circularized three-turn single helical structure. Thus, it is reasonable to assume the possibility for a gradual transition from the CD26 conformations down to the three-turn single helical structure for CD21. The macrorings larger that CD28 most probably can acquire arbitrary shapes with multiple small cavities. All results from our studies are in a support for the domination of representative preferred conformations with a specific shape of the smaller-size LR-CDs (CDn, n=10 to 30) for different ranges of the number of residues.

Keywords: Large-ring cyclodextrins, Conformations and macroring conformational dynamics, Molecular dynamics, Principal Component Analysis, glucanotransferases, enzyme-like, cyclohexaicosaose, Crystallization, CYCLODEXTRINS