title: Theoretical investigation on the glycan-binding specificity of Agrocybe cylindracea galectin using molecular modeling and molecular dynamics simulation studies.
abstract: Galectins are β-galactoside binding proteins which have the ability to serve as potent antitumor, cancer biomarker, and induce tumor cell apoptosis. Agrocybe cylindracea galectin (ACG) is a fungal galectin which specifically recognizes α(2,3)-linked sialyllactose at the cell surface that plays extensive roles in the biological recognition processes. To investigate the change in glycan-binding specificity upon mutations, single point and double point site-directed in silico mutations are performed at the binding pocket of ACG. Molecular dynamics (MD) simulation studies are carried out for the wild-type (ACG) and single point (ACG1) and double point (ACG2) mutated ACGs to investigate the dynamics of substituted mutants and their interactions with the receptor sialyllactose. Plausible binding modes are proposed for galectin-sialylglycan complexes based on the analysis of hydrogen bonding interactions, total pair-wise interaction energy between the interacting binding site residues and sialyllactose and binding free energy of the complexes using molecular mechanics-Poisson-Boltzmann surface area. Our result shows that high contribution to the binding in different modes is due to the direct and water-mediated hydrogen bonds. The binding specificity of double point mutant Y59R/N140Q of ACG2 is found to be high, and it has 26 direct and water-mediated hydrogen bonds with a relatively low-binding free energy of -47.52 ± 5.2 kcal/mol. We also observe that the substituted mutant Arg59 is crucial for glycan-binding and for the preference of α(2,3)-linked sialyllactose at the binding pocket of ACG2 galectin. When compared with the wild-type and single point mutant, the double point mutant exhibits enhanced affinity towards α(2,3)-linked sialyllactose, which can be effectively used as a model for biological cell marker in cancer therapeutics.
authors.affiliation: Department of Physics, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu, 627012, India.
authors.forename: Ponnusamy
authors.initials: P
authors.lastname: Parasuraman
authors.affiliation: Department of Physics, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu, 627012, India.
authors.forename: Veeramani
authors.initials: V
authors.lastname: Murugan
authors.affiliation: Department of Physics, NMSSVN College, Madurai, Tamil Nadu, 625019, India.
authors.forename: Jeyasigamani F A
authors.initials: JF
authors.lastname: Selvin
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India.
authors.forename: M Michael
authors.initials: MM
authors.lastname: Gromiha
authors.affiliation: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukui
authors.affiliation: School of Advanced Sciences, VIT University, Vellore, Tamil Nadu, 632014, India.
authors.forename: Kasinadar
authors.initials: K
authors.lastname: Veluraja
mesh_terms: D055362:Agrocybe / Q000378:metabolism*; D037161:Galectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006860:Hydrogen Bonding; D007785:Lactose / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012794:Sialic Acids / Q000737:chemistry / Q000378:metabolism
chemical_list: D037161:Galectins; D011134:Polysaccharides; D012794:Sialic Acids; C000020:N-acetylneuraminoyllactose; D007785:Lactose
keywords: binding free energy; binding specificity; cancer biomarker; fungal galectin; hydrogen bonds; lectin-carbohydrate interactions; molecular dynamics; sialylglycans