title: Chondrotinase ABC I thermal stability is enhanced by site-directed mutagenesis: a molecular dynamic simulations approach.
abstract: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of growth in the adult central nervous system. Use of the enzyme chondroitinase ABC I (ChABC I) as a strategy to reduce CSPG inhibition in experimental models of spinal cord injury has led to observations of its remarkable capacity for repair. More importantly, ChABC therapy has been demonstrated to promote significant recovery of function to spinal injured animals. Despite this incomparable function of ChABC I, its clinical application has been limited because of its thermal instability as reported in the literature. In a recent study by Nazari-Robati et al., thermal stability of ChABC I was improved by protein engineering using site-directed mutagenesis method. Here, in this study, molecular dynamics simulations were used to take a closer look into the phenomenon leading to the experimentally observed thermal stability improvement followed by the corresponding site-directed mutagenesis. We concluded that the mutations induce local flexibility along with a re-conformation into the native structure which consequently increase the protein thermal stability.
authors.affiliation: a Razi Drug Research Center, Iran University of Medical Sciences , Tehran , Iran.|b Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Medicinal Chemistry , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Kowsar
authors.initials: K
authors.lastname: Bagherzadeh
authors.affiliation: c Department of Clinical Biochemistry , School of Medicine, Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Monireh
authors.initials: M
authors.lastname: Maleki
authors.affiliation: c Department of Clinical Biochemistry , School of Medicine, Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Golestani
authors.affiliation: d Faculty of Biological Sciences , Department of Biochemistry, Tarbiat Modares University , Tehran , Iran.
authors.forename: Khosro
authors.initials: K
authors.lastname: Khajeh
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Medicinal Chemistry , Tehran University of Medical Sciences , Tehran , Iran.
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D019765:Chondroitin ABC Lyase / Q000737:chemistry* / Q000235:genetics; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000737:chemistry*; D004195:Disease Models, Animal; D004795:Enzyme Stability; D006801:Humans; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D013696:Temperature
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D019765:Chondroitin ABC Lyase
keywords: Ramachandran; chondrotinase ABC I; conformational changes; molecular dynamics simulations (MDs); site-directed mutagenesis; thermal stability