Molecular dynamics simulations in water solution were performed on six large-ring cyclodextrins (LR-CDs) with a degree of polymerization 24, 25, 26, 27, 28, and 29. The AMBER parm99 force field and explicit water molecules (TIP3P) were used in the simulations. The present research was aimed at further extending our knowledge on the structural dynamics and the energetics of this new class of compounds that may eventually provide chiral cavities suitable for formation of inclusion complexes with small molecules, and, accordingly, to serve as host structures for chiral recognition. The study focused on several representatives flanking CD26-the largest LR-CD for which X-ray data is available. Both the monitoring of the structural variations during the simulations as well as the analyses of energy balances are indicative for high flexibility of the macrorings. Slight differences of the overall preferred shapes were detected with diminishing the size of the macromolecules from CD29 to CD24. An elongated cavity (CD28) or a double parallel strand in different specific representations are the dominating motifs in the LR-CDs studied: with loops at the two ends (CD25, CD28, CD29), with a loop at one end (CD25), twisted (CD26, CD27) or twisted with an open portion in the middle (CD24), helical (CD24, CD25), or linking two loops from one of their sides (CD27). Two loops connected by an arc (CD28, CD29) and a cavity with the shape of an extended rectangular (CD24, CD28) appear preferentially during the conformational interconversions of the two larger CDs, whereas helical motifs are present in the smaller macrorings: an extended helix with ends linked by an arc (CD24), helical turn and helical portion (CD26, CD27). A triple propeller conformation or three symmetrical loops of almost equal size were also detected for CD26 and CD29, respectively. The present results further support the hypothesis for the existence of more than one cavity in large-ring cyclodextrins and suggest preferred conformations in water solution for the LR-CDs with degree of polymerization from 24 to 29.

Molecular dynamics (MD) simulations in water solution were performed on six large ring cyclodextrins (LR-CDs) with a degree of polymerization (DP) 24,25, 27,28,29, and 30, using as starting structures geometries derived from CD26, which was studied previously by MD. The present research was aimed at further extending our knowledge on the structural dynamics and the energetics of this new class of compounds, focusing on several representatives flanking CD26, the largest LR-CD for which X-ray data are available. The most recent parameterization for carbohydrates, Glycam-04, and explicit water molecules (TIP3P) were used in the 10.0-ns simulations. Preceding 10.0-ns simulations of CD26, with the AMBER parm99 force field, revealed that the overall shape of the macromolecule did not change significantly during the last 5.0-ns simulations. We now further test for the probability of prevalence of this conformation by using a different force field and by examining the effect of the size of the macro-ring on the preferred conformations of LR-CDs with DP within a range of 24 -30. Indeed, we found CD26-like geometries present for CD25, CD27, and CD28, which could be interpreted as an indication for an enhanced stability of the CD26 conformation in water solution. Again, we witnessed high flexibility of the macrocycles, and different local structural motifs were detected: twisted helical double parallel strand (CD25, CD30), single helix of three turns (CD29), a spiral (CD25, CD27, CD30), open-shaped loops and helical turns (CD28; "CD26-like geometry"), a rectangular cavity (CD24), a triple-lobe fragment (CD29) or a portion shaped like a jaw (CD24, CD27), and an overall shape of the macromolecule that resembled a butterfly (CD27) or "X" (CD28). Thus, we conclude that the same conformation of CD26 could be also the preferred conformation in water solution of other LR-CDs with DP in the close vicinity of 26. Wiley Periodicals, Inc. Int J Quantum Chem 107: 1657-1672, 2007 Key words: cyclodextrins; molecular dynamics; conformational analysis; AMBER Introduction A new class of compounds, the large-ring cyclodextrins (LR-CDs) [1] attracted attention in recent years. Advances were marked by the study of their physicochemical properties [2], in spite of existing difficulties in their synthesis [3][4][5], isolation, and purification [6 -8]. LR-CDs were first prepared by French et al. [9]. The crystal structure determinations of the CDs composed by 9 [10], 10 [11], 14 [7, 11a], and 26 [12] glucose units provided information on the conformations of these molecules in the crystal lattice. New structural motifs were detected, and it became evident that their geometries differ considerably from the native CDs (i.e., those composed of 6, 7, and 8 glucose units). More recently, the thermal and structural characterization of ␦-CD, -CD, and -CD have been carried out [13], and references to CDs with more than 60 [14] and several hundred [15] glucose units have been made. The 13 C nuclear magnetic resonance (NMR) spectra in D 2 O at...

Molecular dynamics simulations in water were performed on the three largest large-ring cyclodextrins (LR-CD) for which X-ray data is available -CD10, CD14 and CD26. The Glycam-04 force field in AMBER and explicit water molecules (TIP3P) were used in the 20.0 ns simulations. Small variations about the starting conformation of CD10 were detected. Different structural motifs were monitored for CD14 that may represent chiral species of particular interest for exploring supramolecular and chiral molecular recognition effects: broadly opened macroring, that resembles the initial geometry of CD10 but in larger scale, a big circular loop with a small helical turn, deformed figure eight conformation, and a symmetrically squeezed open form ("a dumbbell"). The final geometry of CD14 is free of additional strain introduced by band-flips. The preferred conformation of CD26 contains a small helix and an extended helical portion that transforms also to an arc and a loop. Two modifications of the equilibration step of the simulation protocol were tested.