A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory complex I.
Int J Biol Macromol
; 273(Pt 2): 133086, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38871105
ABSTRACT
Variants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establish a priori whether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations aimed at investigating new CI variants. One of the primary CI variants associated with the Leber hereditary optic neuropathy (m.14484T>C/MT-ND6) was used as a test case and was investigated alone or in combination with two additional rare CI variants whose role remains uncertain. We found that the primary variant positioned in the E-channel region, which is fundamental for CI function, stiffens the enzyme dynamics. Moreover, a new mechanism for the transition between π- and α-conformation in the helix carrying the primary variant is proposed. This may have implications for the E-channel opening/closing mechanism. Finally, our findings show that one of the rare variants, located next to the primary one, further worsens the stiffening, while the other rare variant does not affect CI function. This approach may be extended to other variants candidate to exert a pathogenic impact on CI dynamics, or to investigate the interaction of multiple variants.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutação de Sentido Incorreto
/
Complexo I de Transporte de Elétrons
/
Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Revista:
Int J Biol Macromol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Itália