title: Modeling conformational redox-switch modulation of human succinic semialdehyde dehydrogenase.
abstract: Succinic semialdehyde dehydrogenase (SSADH) converts succinic semialdehyde (SSA) to succinic acid in the mitochondrial matrix and is involved in the metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The molecular structure of human SSADH revealed the intrinsic regulatory mechanism--redox-switch modulation--by which large conformational changes are brought about in the catalytic loop through disulfide bonding. The crystal structures revealed two SSADH conformations, and computational modeling of transformation between them can provide substantial insights into detailed dynamic redox modulation. On the basis of these two clear crystal structures, we modeled the conformational motion between these structures in silico. For that purpose, we proposed and used a geometry-based coarse-grained mathematical model of long-range protein motion and the related modeling algorithm. The algorithm is based on solving the special optimization problem, which is similar to the classical Monge-Kantorovich mass transportation problem. The modeled transformation was supported by another morphing method based on a completely different framework. The result of the modeling facilitates better interpretation and understanding of the SSADH biological role.
authors.affiliation: Department of Biology, Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Gaik
authors.initials: G
authors.lastname: Tamazian
authors.affiliation: Department of Biology, Teachers College, Kyungpook National University, Daegu, Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Ho Chang
authors.affiliation: Laboratory of Bioinformatics, ITMO University, St. Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Knyazev
authors.affiliation: Laboratory of Bioinformatics, ITMO University, St. Petersburg, Russia.|Laboratory of Representation Theory and Dynamical Systems, St. Petersburg Branch of the Steklov Mathematical Institute of the Russian Academy of Sciences, St. Petersburg, Russia.|Department of Mathematical Physics Faculty of Mathematics and Mechanics, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Stepanov
authors.affiliation: Structural and Molecular Biology Laboratory, School of Life Sciences, KNU Creative BioResearch Group (BK21 Plus Program), Kyungpook National University, Daegu, Korea.
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Laboratory of Bioinformatics, ITMO University, St. Petersburg, Russia.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Porozov
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D050644:Succinate-Semialdehyde Dehydrogenase / Q000737:chemistry*
chemical_list: D004220:Disulfides; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase
keywords: coarse-grained model; conformational motion; morphing; motion simulation; protein mobility