The structural stability of monomeric glucose-6-phosphate dehydrogenase and its relationship to G6PD deficiency

Nhung T. T. Nguyen; Hoang Phong Le; Thi Hai Yen Nguyen; Phuong Thuy Bui; Thi Lan Mai; Xuan Hoang Trinh

doi:10.15625/0868-3166/24093

Author affiliations

Authors

Nhung T. T. Nguyen Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Nghia Do, Hanoi 11307, Vietnam; Institute of Physics, Vietnam Academy of Science and Technology https://orcid.org/0000-0002-2797-1064
Le Hoang Phong Institute of Physics, Vietnam Academy of Science and Technology, 10 Dao Tan, Giang Vo, Hanoi 11108, Vietnam https://orcid.org/0009-0002-3578-4346
Nguyen Thi Hai Yen Institute of Physics, Vietnam Academy of Science and Technology, 10 Dao Tan, Giang Vo, Hanoi 11108, Vietnam https://orcid.org/0000-0002-3640-8505
Phuong Thuy Bui Institute of Theoretical and Applied Research, Duy Tan University, Hanoi, 100000, Vietnam; Faculty of Pharmacy, Duy Tan University, Da Nang, 550000, Vietnam https://orcid.org/0000-0002-9055-9777
Mai Thi Lan Faculty of Engineering Physics, Hanoi University of Science and Technology, 1 Dai Co Viet Road, Hanoi, Vietnam
Trinh Xuan Hoang Institute of Physics, Vietnam Academy of Science and Technology, 10 Dao Tan, Giang Vo, Hanoi 11108, Vietnam https://orcid.org/0000-0002-2672-562X

DOI:

https://doi.org/10.15625/0868-3166/24093

Keywords:

molecular dynamics, protein stability, enzyme activity, mutations

Abstract

G6PD deficiency, an enzymopathy associated with glucose-6-phosphate dehydrogenase (G6PD), is caused by genetic mutations that reduce the enzyme activity, resulting in hemolytic anemia. Biochemical studies have shown that G6PD deficiency in various variants is associated with reduced thermal stability, reduced catalytic activity, or both. In this study, we investigate the
structural stability of the wild-type G6PD monomer at a physiological temperature using molecular dynamics simulations, in the absence and in the presence of its G6P and NADP⁺ ligands. We find that the G6P ligand has a low affinity for the G6PD monomer, which may result from fluctuations in the size of its binding pocket. This finding is consistent with and helps explain the catalytic
inactivity of monomeric G6PD. Our analysis also shows that, with a statistically significant confidence, class I mutations occur preferentially at residues that are more flexible than randomly selected residues, whereas class II mutations tend to occur at residues that are less flexible than randomly selected ones. This result reflects the distinct structural roles of the G6PD mutation sites and further supports the relationship between enzyme activity and thermal stability.

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