Vina-Carb: Improving Glycosidic Angles during Carbohydrate Docking.

Molecular docking programs are primarily designed to align rigid, drug-like fragments into the binding sites of macromolecules and frequently display poor performance when applied to flexible carbohydrate molecules. A critical source of flexibility within an oligosaccharide is the glycosidic linkages. Recently, Carbohydrate Intrinsic (CHI) energy functions were reported that attempt to quantify the glycosidic torsion angle preferences. In the present work, the CHI-energy functions have been incorporated into the AutoDock Vina (ADV) scoring function, subsequently termed Vina-Carb (VC). Two user-adjustable parameters have been introduced, namely, a CHI- energy weight term (chi_coeff) that affects the magnitude of the CHI-energy penalty and a CHI-cutoff term (chi_cutoff) that negates CHI-energy penalties below a specified value. A data set consisting of 101 protein-carbohydrate complexes and 29 apoprotein structures was used in the development and testing of VC, including antibodies, lectins, and carbohydrate binding modules. Accounting for the intramolecular energies of the glycosidic linkages in the oligosaccharides during docking led VC to produce acceptable structures within the top five ranked poses in 74% of the systems tested, compared to a success rate of 55% for ADV. An enzyme system was employed in order to illustrate the potential application of VC to proteins that may distort glycosidic linkages of carbohydrate ligands upon binding. VC represents a significant step toward accurately predicting the structures of protein-carbohydrate complexes. Furthermore, the described approach is conceptually applicable to any class of ligands that populate well-defined conformational states.

[1]  Saul Wolfe,et al.  Gauche effect. Stereochemical consequences of adjacent electron pairs and polar bonds , 1972 .

[2]  R. Lemieux,et al.  The Exo-Anomeric Effect , 1979 .

[3]  H. Tanaka,et al.  The roles of conserved aromatic amino-acid residues in the active site of human lysozyme: a site-specific mutagenesis study. , 1987, Biochimica et biophysica acta.

[4]  M. Cygler,et al.  Recognition of a cell-surface oligosaccharide of pathogenic Salmonella by an antibody Fab fragment. , 1991, Science.

[5]  M. Cygler,et al.  Recognition of a carbohydrate antigenic determinant of Salmonella by an antibody. , 1993, Biochemical Society transactions.

[6]  Y. Li,et al.  Structure of a single-chain antibody variable domain (Fv) fragment complexed with a carbohydrate antigen at 1.7-A resolution. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Brisson,et al.  Solution structure of a trisaccharide-antibody complex: comparison of NMR measurements with a crystal structure. , 1994, Biochemistry.

[8]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[9]  A. Imberty,et al.  Oligosaccharide structures: theory versus experiment. , 1997, Current opinion in structural biology.

[10]  Karl N. Kirschner,et al.  Solvent interactions determine carbohydrate conformation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Ruth Nussinov,et al.  Principles of docking: An overview of search algorithms and a guide to scoring functions , 2002, Proteins.

[12]  Peter J. Reilly,et al.  Specific empirical free energy function for automated docking of carbohydrates to proteins , 2003, J. Comput. Chem..

[13]  Alexander Isaev,et al.  PyEvolve: a toolkit for statistical modelling of molecular evolution , 2004, BMC Bioinformatics.

[14]  Martin Stahl,et al.  Scoring functions for protein-ligand interactions: a critical perspective. , 2004, Drug discovery today. Technologies.

[15]  Claus-Wilhelm von der Lieth,et al.  pdb-care (PDB CArbohydrate REsidue check): a program to support annotation of complex carbohydrate structures in PDB files , 2004, BMC Bioinformatics.

[16]  Martin Frank,et al.  GLYCOSCIENCES.de: an Internet portal to support glycomics and glycobiology research. , 2006, Glycobiology.

[17]  Oliver Kohlbacher,et al.  SLICK — Scoring and Energy Functions for Protein—Carbohydrate Interactions. , 2006 .

[18]  K. Sakka,et al.  Crystal Structure of Cel44A, a Glycoside Hydrolase Family 44 Endoglucanase from Clostridium thermocellum* , 2007, Journal of Biological Chemistry.

[19]  Karl Nicholas Kirschner,et al.  GLYCAM06: A generalizable biomolecular force field. Carbohydrates , 2008, J. Comput. Chem..

[20]  Richard A. Friesner,et al.  Small Molecule Docking , 2008 .

[21]  Dirk Neumann,et al.  BALLDock/SLICK: A New Method for Protein-Carbohydrate Docking , 2008, J. Chem. Inf. Model..

[22]  F. Saul,et al.  Structures of synthetic O-antigen fragments from serotype 2a Shigella flexneri in complex with a protective monoclonal antibody , 2008, Proceedings of the National Academy of Sciences.

[23]  Manuel C. Peitsch,et al.  Computational structural biology : methods and applications , 2008 .

[24]  Kerry Gordon,et al.  A game of snakes and ladders , 2008 .

[25]  Robert J Woods,et al.  Structural glycobiology: A game of snakes and ladders , 2008, Glycobiology.

[26]  J. Gildersleeve,et al.  Glycan arrays: recent advances and future challenges. , 2009, Current opinion in chemical biology.

[27]  Maureen E. Taylor,et al.  Structural insights into what glycan arrays tell us about how glycan-binding proteins interact with their ligands , 2009, Glycobiology.

[28]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[29]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[30]  M. Teresa Pisabarro,et al.  Docking glycosaminoglycans to proteins: analysis of solvent inclusion , 2011, J. Comput. Aided Mol. Des..

[31]  H. Gilbert,et al.  Understanding How Noncatalytic Carbohydrate Binding Modules Can Display Specificity for Xyloglucan , 2012, The Journal of Biological Chemistry.

[32]  M. Parker,et al.  Manipulating the Lewis antigen specificity of the cholesterol-dependent cytolysin lectinolysin , 2012, Front. Immun..

[33]  Diego F. Gauto,et al.  Solvent structure improves docking prediction in lectin-carbohydrate complexes. , 2013, Glycobiology.

[34]  Bethany Lachele Foley,et al.  Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff , 2014, J. Comput. Chem..

[35]  Bethany Lachele Foley,et al.  BFMP: A Method for Discretizing and Visualizing Pyranose Conformations , 2014, J. Chem. Inf. Model..

[36]  Robert J Woods,et al.  Recent advances in employing molecular modelling to determine the specificity of glycan-binding proteins. , 2014, Current opinion in structural biology.

[37]  Kevin Cowtan,et al.  Carbohydrate anomalies in the PDB. , 2015, Nature chemical biology.