Molecular dynamics simulations revealed topological frustration in the binding-wrapping process of eIF4G with eIF4E.
Phys Chem Chem Phys
; 26(3): 2073-2081, 2024 Jan 17.
Article
em En
| MEDLINE
| ID: mdl-38131207
ABSTRACT
Interaction between the cap-binding protein eIF4E and the scaffolding protein eIF4G is essential for the cap-dependent translation initiation in eukaryotes. In the Saccharomyces cerevisiae eIF4G/eIF4E complex, the intrinsically disordered eIF4E-binding domain of eIF4G folds into a bracelet-like structure upon binding to eIF4E. Aiming to unveil the molecular mechanism underlying the binding-wrapping process of eIF4G with eIF4E, we performed extensive coarse-grained molecular dynamics simulations and transition path analysis in this work. The major transition pathway revealed from our simulations showed that docking of the eIF4E-binding motif of eIF4G to the folded core of eIF4E initiates the binding process and then the disordered eIF4G wraps around the N-terminal tail of eIF4E. Additionally, we identified a minor transition pathway which indicates the involvement of topological frustration in the binding process. By manipulating the interaction strength of the wrapping contacts and the latching contacts, we further dissected factors affecting the formation of topological frustration and the binding transition kinetics. Our findings provide new clues for experimental studies on the binding mechanism of eIF4G to eIF4E in the future and exemplify the involvement of topological frustration in the binding process of intrinsically disordered proteins.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Iniciação 4E em Eucariotos
/
Fator de Iniciação Eucariótico 4G
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article