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

Author(s)

Hernandez-Alvarez, Lilian ^[1] ; Oliveira Jr, Antonio B. ; Hernandez-Gonzalez, Jorge Enrique ^{[2, 3]} ; Chahine, Jorge ^[3] ; Pascutti, Pedro Geraldo ^[2] ; de Araujo, Alexandre Suman ^[3] ; de Souza, Fatima Pereira ^[3]

Affiliation

^[1] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Phys, Sao Jose Do Rio Preto, SP - Brazil

^[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Rio de Janeiro - Brazil

^[3] Oliveira Jr, Jr., Antonio B., Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Phys, Sao Jose Do Rio Preto, SP - Brazil

• Document type: Journal article
• Source: COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL; v. 19, p. 2027-2044, 2021.
• Web of Science Citations: 0

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 (Delta G(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 Delta G(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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. (AU)

• FAPESP's process: 10/18169-3 - Investigations of physical chemistry processes related with the binding of environmental relevant heavy metal ions by calix[4]arenes using molecular dynamics simulations
• Grantee: Alexandre Suman de Araujo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain
• Grantee: Lilian Hernández Alvarez
• Support Opportunities: Scholarships in Brazil - Doctorate