The article reviews the significant contributions to, and the present status of, applications of computational methods for the characterization and prediction of protein-carbohydrate interactions. After a presentation of the specific features of carbohydrate modeling, along with a brief description of the experimental data and general features of carbohydrate-protein interactions, the survey provides a thorough coverage of the available computational methods and tools. At the quantum-mechanical level, the use of both molecular orbitals and density-functional theory is critically assessed. These are followed by a presentation and critical evaluation of the applications of semiempirical and empirical methods: QM/MM, molecular dynamics, free-energy calculations, metadynamics, molecular robotics, and others. The usefulness of molecular docking in structural glycobiology is evaluated by considering recent docking- validation studies on a range of protein targets. The range of applications of these theoretical methods provides insights into the structural, energetic, and mechanistic facets that occur in the course of the recognition processes. Selected examples are provided to exemplify the usefulness and the present limitations of these computational methods in their ability to assist in elucidation of the structural basis underlying the diverse function and biological roles of carbohydrates in their dialogue with proteins. These test cases cover the field of both carbohydrate biosynthesis and glycosyltransferases, as well as glycoside hydrolases. The phenomenon of (macro)molecular recognition is illustrated for the interactions of carbohydrates with such proteins as lectins, monoclonal antibodies, GAG-binding proteins, porins, and viruses.

Carbohydrate-protein interactions: molecular modeling insights

The conformation and structure of GAGs: recent progress and perspectives.

Depiction of the forces participating in the 2-O-sulfo-α-l-iduronic acid conformational preference in heparin sequences in aqueous solutions

The solution conformation of a fully sulfated heparin-derived tetrasaccharide, I, was studied in the presence of a 4-fold excess of Ca(2+). Proton-proton and proton-carbon residual dipolar couplings (RDCs) were measured in a neutral aligning medium. The order parameters of two rigid hexosamine rings of I were determined separately using singular value decomposition and ab initio structures of disaccharide fragments of I. The order parameters were very similar implying that a common order tensor can be used to analyze the structure of I. Using one order tensor, RDCs of both hexosamine rings were used as restraints in molecular dynamics simulations. RDCs of the inner iduronic acid were calculated for every point of the molecular dynamics trajectory. The fitting of the calculated RDCs of the two forms of the iduronic acid to the experimental values yielded a population of (1)C(4) and (2)S(o) conformers of iduronic acid that agreed well with the analysis based on proton-proton scalar coupling constants. The glycosidic linkage torsion angles in RDC-restrained molecular dynamics (MD) structures of I are consistent with the interglycosidic three-bond proton-carbon coupling constants. These structures also show that the shape of heparin is not affected dramatically by the conformational flexibility of the iduronic acid ring. This is in line with conclusions of previous studies based on MD simulations and the analysis of (1)H-(1)H NOEs. Our work therefore demonstrates the effectiveness of RDCs in the conformational analysis of glycosaminoglycans.

Residual dipolar coupling investigation of a heparin tetrasaccharide confirms the limited effect of flexibility of the iduronic acid on the molecular shape of heparin.

The fragment molecular orbital method (FMO) was applied to the geometry optimization of several heparin oligosaccharides at the RHF/6-31(+)G(d) level combined with the polarizable continuum model (PCM). For comparison, GLYCAM force field optimization in explicit solvent was also conducted. Good accuracy of FMO was demonstrated in comparison to ab initio at the MP2/PCM level. The interaction analysis was conducted using the pair interaction energy decomposition analysis (PIEDA), and the role of hydrogen bonding and solvent was elucidated in the helix formation of heparin in solution. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2009

E. Scholtzová

Papers

B3LYP/6-311++G∗∗ study of structure and spin–spin coupling constant in heparin disaccharide