Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition

Lilian Hernández-Alvarez; Antonio B Oliveira Jr; Jorge Enrique Hernández-González; Jorge Chahine; Pedro Geraldo Pascutti; Alexandre Suman de Araujo; Fátima Pereira de Souza

doi:10.1016/j.csbj.2021.03.036

Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m⁷GTP cap recognition

Comput Struct Biotechnol J. 2021 Apr 5:19:2027-2044. doi: 10.1016/j.csbj.2021.03.036. eCollection 2021.

Authors

Lilian Hernández-Alvarez¹, Antonio B Oliveira Jr^{1

2}, Jorge Enrique Hernández-González^{1

3}, Jorge Chahine¹, Pedro Geraldo Pascutti³, Alexandre Suman de Araujo¹, Fátima Pereira de Souza¹

Affiliations

¹ Department of Physics, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio Preto, São Paulo, Brazil.
² Center for Theoretical Biological Physics, Rice University, Huston, TX, United States.
³ Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Abstract

During their life cycle, Leishmania 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 L. major 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 (ΔG_bind ) 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 ΔG_bind 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.

Keywords: 4E-binding proteins; Adaptive Biasing Force (ABF) calculations; Allostery; Eukaryotic Initiation Factor-4E; Leishmania major; Molecular dynamics; mRNA cap.