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J. Phys. Chem. B 2010, 114, 2650–2659
Conformations of Some Large-Ring Cyclodextrins Derived from Conformational Search with Molecular Dynamics Simulations and Principal Component Analysis Petko M. Ivanov* Laboratory of Physical Organic and Computational Chemistry, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, ul. Acad. G. BoncheV, bloc 9, 1113 Sofia, Bulgaria ReceiVed: NoVember 20, 2009; ReVised Manuscript ReceiVed: January 18, 2010
Principal component analysis (PCA) was applied for postprocessing of trajectories from conformational search, based on 50.0 ns molecular dynamics (MD) simulations, with the purpose to elucidate the conformations of some large-ring cyclodextrins (LR-CDs), CDn (n ) 24, 25, 26, 27, 28, 29). The dominant PCA modes for concerted motions of the macroring atoms were monitored in a lower-dimension subspace. The first 10 lowest indexed modes describe more than 90% of the total atomic motions in all cases, with about 85% (CD27, CD29) to more than 90% (CD24, CD25) contribution coming from the six highest-eigenvalue principal components. Representative average geometries of the cyclodextrin macrorings were also obtained for the whole simulation and for the five 10.0 ns time intervals of the simulation. Two conformations for CD26, the largest LR-CD for which X-ray data is available, are characterized by possessing, respectively, one and two helical turns. Resemblance to computed representative conformations of CD26 in water was found for CD27 and CD28, with the similarity being better expressed for the former case. Only CD24, among the two smaller size LR-CDs, displays resemblance during short simulation intervals to one of the conformations of CD26. The formation of small loops of six to seven glucose units is a favorable deformation mode of the macrorings. Besides, once a small loop of six to seven glucoses is formed, the next natural mode for deformation of the macromolecule is toward the creation of a short helix that further enhances the stability of the structure. The average geometry of CD29 has no likeness at all to the conformations of CD26. Thus, the difference of three glucose units between CD26 and CD29 already influences significantly the shape of the most probable conformation. Introduction The information about the preferred conformations of largering cyclodextrins (LR-CDs)1-4 is still very limited, although advances were marked in recent years in the study of their physicochemical properties.5-14 Crystal structure determinations were so far successful only for the CDs composed by 9,15 10,13,16,17 14,13,16 and 2618,19 glucose units.20 New structural motifs were detected, and it became evident that their geometries differ considerably from the native CDs (i.e., those composed of 6 (R-CD), 7 (β-CD), and 8 (γ-CD) glucose units). The thermal and structural characterization of δ-CD, ε-CD, and ι-CD have been carried out,21 and references to CDs with more than 6022 and several hundred23 glucose units have been made. Since CDs consist of optically active D-glucose units, they form with a racemic compound a pair of diastereoisomeric complexes, usually of different stability. Therefore, LR-CDs, as the native CDs,24-26 are potential reagents for chiral resolution, which is of practical importance for separation science (molecular recognition and separation of closely related compounds, including geometrical and structural isomers) and for the pharmaceutical industry (different pharmacological activity of enantiomers of a chiral compound).24 LR-CDs may be good host molecules for relatively large guest compounds.5 Ueda summarized in a mini-review the results about LR-CDs with regard to the potential for host-guest interactions and corresponding applications (commercially available CD mixtures containing LR-CDs with a degree of polymerization from 9 to * E-mail:
[email protected].
21 were examined as food additives in Japan;5 LR-CD mixtures with a degree of polymerization from 22 to 45, and greater than 50, exhibited an efficient artificial chaperone effect for protein refolding (the first practical application of LR-CDs)27). The inclusion complexes of CDs of up to 17 glucose units with several benzoates, salicylate, ibuprofen anion, and 1-adamantane carboxylate have been studied, and their formation constants have been determined.28 Association constants for those CDs having more than 10 glucoses are usually small (
