Molecular simulations of carbohydrates and protein-carbohydrate interactions: motivation, issues and prospects

Abstract

The characterization of the 3D structure of oligosaccharides, their conjugates and analogs is particularly challenging for traditional experimental methods. Molecular simulation methods provide a basis for interpreting sparse experimental data and for independently predicting conformational and dynamic properties of glycans. Here, we summarize and analyze the issues associated with modeling carbohydrates, with a detailed discussion of four of the most recently developed carbohydrate force fields, reviewed in terms of applicability to natural glycans, carbohydrate-protein complexes and the emerging area of glycomimetic drugs. In addition, we discuss prospectives and new applications of carbohydrate modeling in drug discovery.

FIGURE 1

(a) Structure of the de-esterified form of the neuraminidase inhibitor oseltamivir in complex with the H274Y mutant of influenza virus N1 neuraminidase that displays resistance to treatment with oseltamivir (PDBID 3CL0 [134]). (b) Schematic representations of the natural substrate (neuraminic acid). (c) Schematic representations of the inhibitor.

FIGURE 2

(a) A complex of concanavalin A (ConA) with trimannoside (PDBID 1CVN [55]). (b) A close-up of ConA binding site. Key residues for carbohydrate binding and recognition are highlighted: Asp 16 and Asp 208 in red, Arg 228 in blue, and Asn 14 in purple. The trimannoside is colored according to its atom types. The oxygen of a key water molecule is also represented as a red van der Waals (vdW) sphere.

FIGURE 3

Detail of a complex between antithrombin (AT3) and heparin (PDBID 1SR5 [135]). Heparin is colored according to its atom types, and two Phe keys for heparin binding are highlighted in purple. The Arg and Lys residues in the binding site are shown in light gray.

FIGURE 4

Illustration of the φ, ψ and ω dihedral angles for a representative 1–4 linked disaccharide (maltose).

FIGURE 5

Newman projections of the gauche-gauche (gg), gauche-trans (gt) and trans-gauche (tg) rotameric conformers of the ω dihedral angle. The gg, gt and tg conformers are defined relative to the O5-C5-C6-O6 and C4-C5-C6-O6 torsions.

FIGURE 6

Approximate estimate of the usage of carbohydrate force fields developed after 1990; namely, GLYCAM, AMBER, CHARMM, OPLS-AA, GROMOS, MM4 [–138] and SPASIBA [139]. Each slice is proportional to the number of citations of the seminal force field paper in the past five years, according to the ISI `Web of Science' (http://scientific.thomsonreuters.com/products/wos/).