title: Modelling family 2 cystatins and their interaction with papain.
abstract: Cystatins are extensively studied cysteine protease inhibitors, found in wide range of organisms with highly conserved structural folds. S-type of cystatins is well known for their abundance in saliva, high selectivity and poorer activity towards host cysteine proteases in comparison to their immediate ancestor cystatin C. Despite more than 90% sequence similarity, the members of this group show highly dissimilar binding affinity towards papain. Cystatin M/E is a potent inhibitor of legumain and papain like cysteine proteases and recognized for its involvement in skin barrier formation and potential role as a tumor suppressor gene. However, the structures of these proteins and their complexes with papain or legumain are still unknown. In the present study, we have employed computational methods to get insight into the interactions between papain and cystatins. Three-dimensional structures of the cystatins are generated by homology modelling, refined with molecular dynamics simulation, validated through numerous web servers and finally complexed with papain using ZDOCK algorithm in Discovery Studio. A high degree of shape complementarity is observed within the complexes, stabilized by numerous hydrogen bonds (HB) and hydrophobic interactions. Using interaction energy, HB and solvent accessible surface area analyses, we have identified a series of key residues that may be involved in papain-cystatin interaction. Differential approaches of cystatins towards papain are also noticed which are possibly responsible for diverse inhibitory activity within the group. These findings will improve our understanding of fundamental inhibitory mechanisms of cystatin and provide clues for further research.
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, 741235, India.
authors.forename: Suman Kumar
authors.initials: SK
authors.lastname: Nandy
authors.forename: Rajabrata
authors.initials: R
authors.lastname: Bhuyan
authors.forename: Alpana
authors.initials: A
authors.lastname: Seal
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010206:Papain / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D055333:Salivary Cystatins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D055333:Salivary Cystatins; D010206:Papain