title: Docking, molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease.
abstract: The disruption of aspartoacylase enzyme's catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients' genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations.
authors.affiliation: Department of Chemistry, Gebze Technical University, 41400 Kocaeli, Turkey. Electronic address: kocak@gtu.edu.tr.
authors.forename: Abdulkadir
authors.initials: A
authors.lastname: Kocak
authors.affiliation: Department of Molecular Biology and Genetics, Gebze Technical University, 41400 Kocaeli, Turkey.
authors.forename: Muslum
authors.initials: M
authors.lastname: Yildiz
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry* / Q000235:genetics; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D017825:Canavan Disease / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase
keywords: ASPA; Canavan; Docking; Molecular dynamics; Mutation; Neurodegenerative