Conformation in carbohydrates

R. U. Lemieux Application of nuclear magnetic resonance to problems of structure, configuration, and conformation in carbohydrate chemistry J. S. Brimacombe Synthesis of some naturally occurring allose derivatives and some associated chemistry... 

Any molecule of a given configuration can exist in different spatial arrangements (conformations) when the atoms or atomic groups are rotated or twisted with respect to each other within the limits permitted by the bonds. Although the concept of conformation in carbohydrate chemistry is old (Haworth, 1929), novel studies during the last three decades, especially by Barton and Hassel (Nobel Prize in 1969), have added clarity and important details to this concept. The conformations can best be visualized with the use of molecular models. 

We saw in Chapter 2 that glucose can cyclize to form either the a ox hemiacetal. All of the substituents on the tetrahydropyran ring of glucose are equatorial except for the hemiacetal hydroxyl group, which may be either axial (for the a anomer) or equatorial (for the 6 anomer). If the conformational preferences of the tetrahydropyran ring are similar to those of cyclohexane, then an A value for OH of 0.87 in a protic solvent would predict that the axial anomer should comprise no more than 10% of the mixture. Experimentally, it has been determined that the a anomer is present to the extent of 34% of the equilibrium population of conformers. In the case of o-marmose, the a anomer (10) is the major isomer, and the )3 anomer (11) comprises only 32% of the equilibrium mixture. This preference for axial conformer in carbohydrates has been termed the anomeric effect. This term is also used for any system R-Y-C-X, where X is an electronegative atom and Y is an atom with at least one lone pair. 

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

The chair conformation of cyclohexane has many consequences. We ll see in Section 1.1.9, for instance, that the chemical behavior of many substituted cyclohexanes is influenced by their conformation. In addition, we ll see in Section 2S.5 that simple carbohydrates such as glucose adopt a conformation based on the cyclohexane chair and that their chemistry is directly affected as a result. 

From the previous discussion, it is clear that relaxation experiments constitute a very powerful tool for investigation of the structure and conformation of carbohydrate molecules in solution. However, the nature of the individual problem may determine which relaxation experiment should be chosen in order to extract interproton distances to the desired accuracy of < 0.2 A. Although the limitations and relative merits of all of the various relaxation methods have not yet been systematically studied, accumulated experience provides some direct knowledge about the range of errors associated with relaxation experiments. 

The branched trisaccharide 1 was defined as the minimal carbohydrate epitope for effective binding to anti-GAS Abs [79]. The bound conformation of 1 in complex with the IgG mAb Strep 9 was investigated by transferred NOE experiments and found to correspond to a local minimum conformation, which differed from the predominant conformation in the free state by a rotation around the xj/ angle of the o -(l-2) linkage [123]. STD-NMR ex-... 

Molecular dynamics (MD) simulations are a class of molecular mechanics calculation which directly model the motions of molecular systems, often providing considerable information which cannot be obtained by any other technique, theoretical or experimental. MD simulations have only recently been applied to problems of carbohydrate conformation and motions, but it is likely that this technique will be widely used for modeling carbohydrates in the future. This paper introduces the basic techniques of MD simulations and illustrates the types of information which can be gained from such simulations by discussing the results of several simulations of sugars. The importance of solvation in carbohydrate systems will also be discussed, and procedures for including solvation in molecular dynamics simulations will be introduced and again illustrated from carbohydrate studies. 

To date, only a few solution calculations for carbohydrates have been attempted (one such study of mannitol and sorbitol is described in the chapter by Grigera in this volume), but the results of these early studies bear out the expectation that solvation effects in carbohydrate systems can be both significant and difficult to predict. In the case of pyranoid rings, molecular solvation is further complicated by the close juxtaposition of these groups in essentially fixed relative orientations (assuming no conformational changes in the ring). Under such circumstances, molecular stereochemistry could play important physical roles, as is... 

The conformers in Figure 2 are named descriptively and given a rotational label using terminology appropriate for acyclic carbohydrate conformers [(5, (pp 182-203)]. 

A coirplete understanding of the role of carbohydrates in biological systems requires knowledge of the distribution at equilibrium of the various conformers in aqueous solution. The conformational behavior of carbohydrates in solution can be examined from different vantage points (1,), but the most relevant approach is, no doubt, study of dilute solutions themselves. At present, high resolution NMR spectroscopy is the primary tool for determination of three-dimensional structure of oligosaccharides in solution. Optical rotation is also very sensitive to conformation (2) and there is a new, semi-enqpirical theory of optical rotation of oligosaccharides ( ). 

The modeling of carbohydrates is undergoing rapid development. For example, the first comprehensive conformational mappings of disaccharides with flexible residues and the first molecular dynamics studies of carbohydrates have only recently been published. At the same time, interest in carbohydrates has been increasing dramatically, and there is a need for a publication that gently introduces the uninitiated and provides an overview of current research in the area. We feel that Computer Modeling ( Carbohydrate Molecules meets these needs. 

The recognition step, the first event in carbohydrate protein interactions, is dependent on the overall conformation of the oUgosac aride in aqueous solution. Therefore, it is important to determine whether the conformational characteristics of the natural compounds are reflected in the substrate analogues. The most usual methods to achieve this goal is the combination of NMR spectroscopy, molecular mechanics calculations and X-ray data. On this basis, only few conformational studies of thiodisaccharides were reported. 

These latter results, together with those previously reported, clearly demonstrate differences between solution and surface conformations. In supramolecu-lar assemblies, the conformation of a carbohydrate does not only results from the arrangement of atoms inside surrounding water or steric hindrance with the carrier (if any) the lipophilic moiety of amphiphilic carbohydrates and the lipi-dic environment also control the conformation of the hydrophilic moiety, and therefore the recognition. 

Several evidences, reported in the literature and briefly reviewed in the present article, demonstrate that the carbohydrate recognition at the surface of organized systems is somewhat different from that observed in isotropic media. These differences lie in (1) the conformation of carbohydrate which is affected by hydrophobization and by the nature of the surrounding lipids, (2) cluster effects from which can result in high energies of binding and which are affected by the fluidity of the lipid system, (3) entropy changes at the surface of a supra-molecular structure. 

New glycolipids have to be synthesized to get further insights into liquid crystal properties (mainly lyotropic liquid crystals), surfactant properties (useful in the extraction of membrane proteins), and factors that govern vesicle formation, stability and tightness. New techniques have to be perfected in order to allow to make precise measurements of thermodynamic and kinetic parameters of binding in 3D-systems and to refine those already avalaible with 2D-arrays. Furthermore, molecular mechanics calculations should also be improved to afford a better modeling of the conformations of carbohydrates at interfaces, in relation with physical measurements such as NMR. 

Recall that in the latter, certain types of substituents adjacent to oxygen in the ring actually prefer axial arrangements. This observation has been codified in what is commonly referred to as the anomeric effect and is responsible in part for the conformations of carbohydrates. Is it possible that conformational preferences seen in substituted tetrahydropyrans will carry over into preferences in transition-state geometries for Claisen rearrangements ... 

Jarvis, M.C., Apperley, D.C. (1995). Chain conformation in concentrated pectic gels evidence from 13CNMR. Carbohydrate Research, 275, 131-145. 

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