Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m 7 GTP cap recognition

• Published in: Computational and structural biotechnology journal Vol. 19; p. 2027
• Main Authors: Hernández-Alvarez, Lilian, Oliveira, Jr, Antonio B, Hernández-González, Jorge Enrique, Chahine, Jorge, Pascutti, Pedro Geraldo, de Araujo, Alexandre Suman, de Souza, Fátima Pereira
• Format: Journal Article
• Language: English
• Published: Netherlands 2021
• Subjects: mRNA cap; Molecular dynamics; Allostery; 4E-binding proteins; Adaptive Biasing Force (ABF) calculations; Eukaryotic Initiation Factor-4E; Leishmania major
• ISSN: 2001-0370; 2001-0370

During their life cycle, parasites display a fine-tuned regulation of the mRNA translation through the differential expression of isoforms of eukaryotic translation initiation factor 4E (LeishIF4Es). The interaction between allosteric modulators such as 4E-interacting proteins (4E-IPs) and LeishIF4E affects the affinity of this initiation factor for the mRNA cap. Here, several computational approaches were employed to elucidate the molecular bases of the previously-reported allosteric modulation in exerted by 4E-IP1 (Lm4E-IP1) on eukaryotic translation initiation factor 4E 1 (LmIF4E-1). Molecular dynamics (MD) simulations and accurate binding free energy calculations (Δ ) were combined with network-based modeling of residue-residue correlations. We also describe the differences in internal motions of LmIF4E-1 apo form, cap-bound, and Lm4E-IP1-bound systems. Through community network calculations, the differences in the allosteric pathways of allosterically-inhibited and active forms of LmIF4E-1 were revealed. The Δ values show significant differences between the active and inhibited systems, which are in agreement with the available experimental data. Our study thoroughly describes the dynamical perturbations of LmIF4E-1 cap-binding site triggered by Lm4E-IP1. These findings are not only essential for the understanding of a critical process of trypanosomatids' gene expression but also for gaining insight into the allostery of eukaryotic IF4Es, which could be useful for structure-based design of drugs against this protein family.