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Modeling conformational redox‐switch modulation of human succinic semialdehyde dehydrogenase
Author(s) -
Tamazian Gaik,
Ho Chang Jeong,
Knyazev Sergey,
Stepanov Eugene,
Kim KyungJin,
Porozov Yuri
Publication year - 2015
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24937
Subject(s) - chemistry , in silico , redox , succinic acid , biophysics , protein data bank (rcsb pdb) , biochemistry , biology , organic chemistry , gene
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. Proteins 2015; 83:2217–2229. © 2015 Wiley Periodicals, Inc.