Computational Studies of Human Galectin-1: Role of Conserved Tryptophan Residue in Stacking Interaction with Carbohydrate Ligands

Abstract Galectins belong to the family of glycan-binding proteins, defined by at least one conserved carbohydrate-recognition domain with a highly conserved amino acid sequence and affinity for β galactosides. They all possess a tryptophan residue in the carbohydrate binding site that forms hydrophobic contacts with the carbohydrate ligands. Site directed mutagenesis experiments have shown that this conserved aromatic residue plays a key role in the interaction. We have studied the interaction between the corresponding human Galectin-1 in silico mutants and different carbohydrate ligands using molecular dynamics in explicit solvent. The results confirm the importance of the conserved tryptophan residue in the affinity of the ligand and gives further insights into the mode of interaction between lactose derivatives and human Galectin-1.

[1]  G. Rabinovich,et al.  Galectin-1 as a potential therapeutic target in autoimmune disorders and cancer , 2008, Expert opinion on biological therapy.

[2]  T. Feizi,et al.  Soluble 14-kDa beta-galactoside-specific bovine lectin. Evidence from mutagenesis and proteolysis that almost the complete polypeptide chain is necessary for integrity of the carbohydrate recognition domain. , 1991, The Journal of biological chemistry.

[3]  G. Ashraf,et al.  Galectins - potential targets for cancer therapy. , 2007, Cancer letters.

[4]  Hans-Joachim Gabius,et al.  Growth-regulatory human galectin-1: crystallographic characterisation of the structural changes induced by single-site mutations and their impact on the thermodynamics of ligand binding. , 2004, Journal of molecular biology.

[5]  M. F. Troncoso,et al.  Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival , 2007, Cellular and Molecular Life Sciences.

[6]  Benjamin G Davis,et al.  Lectins: tools for the molecular understanding of the glycocode. , 2005, Organic & biomolecular chemistry.

[7]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[8]  G. Rabinovich.  Galectin-1 as a potential cancer target , 2005, British Journal of Cancer.

[9]  R. Kiss,et al.  Galectin-1: a small protein with major functions. , 2006, Glycobiology.

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

[11]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[12]  Alexander D. MacKerell,et al.  CH/π interactions involving aromatic amino acids: Refinement of the CHARMM tryptophan force field , 2005, J. Comput. Chem..

[13]  Petety V Balaji,et al.  Identification of common structural features of binding sites in galactose‐specific proteins , 2004, Proteins.

[14]  Alexander D. MacKerell,et al.  Comparison of protein force fields for molecular dynamics simulations. , 2008, Methods in molecular biology.

[15]  B. Dominy,et al.  Development of a generalized Born model parameterization for proteins and nucleic acids , 1999 .

[16]  B. Roux,et al.  Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials. , 2006, Biophysical journal.

[17]  G. Rabinovich,et al.  Functions of cell surface galectin-glycoprotein lattices. , 2007, Current opinion in structural biology.

[18]  V. Castronovo,et al.  Expression of galectins in cancer: A critical review , 2004, Glycoconjugate Journal.

[19]  W. Weis,et al.  Structural basis of lectin-carbohydrate recognition. , 1996, Annual review of biochemistry.

[20]  J Hirabayashi,et al.  Effect of amino acid substitution by sited-directed mutagenesis on the carbohydrate recognition and stability of human 14-kDa beta-galactoside-binding lectin. , 1991, The Journal of biological chemistry.