Large‐ring cyclodextrins. Further support for the preferred conformations of CD26 in water solution: Molecular dynamics studies on CD26‐derived conformations of CDn (n = 24, 25, 27, 28, 29, 30)

Abstract

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...

Large-ring cyclodextrins. A molecular dynamics study of the conformational dynamics and energetics of CD10, CD14 and CD26

“…Differences were obtained here in comparison with all earlier analyses of hydrogen bond distributions, 41,42,51,52 and these discrepancies resulted from the minor variations introduced in the equilibration stage of the simulation protocol (heating of the system from 0 K to 300 K within the first 10000 time-steps by increasing in ten steps the temperature in portions of 30 degrees, plus 90000 time-steps equilibration at 300 K). It appears that some properties, like intermolecular hydrogen bonds distributions are very sensitive to parameters of the simulation protocol.…”

“…Up to now, researchers in the field of cyclodextrins have been focusing their attention at the cavities formed by these macrorings, especially the native CDs. However, the results from our previous studies, 51,52 as well as the present one, with large variety of chiral structural shapes, open the possibility of using not the cavities but the whole macroring as a suitable ligand for some large chiral molecules with chirality originating from the symmetry group to which the molecule belongs, not from the existence of chiral atoms. Due to the flipping of about 180º in anti orientation of two diametrically opposed glucoses along the perimeters of the macrorings, the molecular shapes of CD10 and CD14, determined from X-ray analyses, resemble the shape of a butterfly in which the wings are formed by cyclodextrin-like fragments and the conformational band-flips ("flips") are located at the body.…”

“…41,51 The most representative structural motifs during the simulation are a helical portion, one or two loops and an arc. The only difference in the results from the previous simulation protocol 41,51,52 (data designated with CD26*) is that the first "flip" did not disappear from the very beginning of the simulation, but survived during the first 3.0 ns.…”

“…Additional simulations were executed for CD26 that differ only in step "v)" of the present equilibration protocol. The approach adopted in the previous work was followed, 52 and we designated these data throughout the text by CD26*. We monitored the variations with the simulation time of the temperature of the systems, the pressure on the walls of the boxes, the volumes of the boxes, the density of the solvent, and the relevant energy characteristics (total, kinetic, and potential energies), and they were all indicative of simulations of equilibrated systems.…”

“…We proceed now further by examining in more detail the conformations of the three largest LR-CDs for which X-ray data is available -CD10, CD14 and CD26, using X-ray starting geometries, much longer simulation times (20.0 ns), and the new Glycam-04 force field in AMBER for carbohydrates. 53 Minor variations in the previous simulation protocol 52 were also made, and they appeared to be of importance for the analyses of some properties, like hydrogen bonds distributions.…”