Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Authors

  • Jorge Luis Rosas-Trigueros,

    1. SEPI de la ESCOM del Instituto Politécnico Nacional, Juan de Dios Bátiz y Miguel Othón de Mendizábal s/n, México D.F. 07738, México
    2. Laboratorio de Investigación Bioquímica, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México D.F. 07320, México
    3. Grupo Interdisciplinario de Inteligencia Artificial Aplicada al Plegamiento de Proteínas
    Search for more papers by this author
  • José Correa-Basurto,

    1. Grupo Interdisciplinario de Inteligencia Artificial Aplicada al Plegamiento de Proteínas
    2. Laboratorio de Modelado Molecular y Bioinformática-SEPI de la ESM del Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México D.F. 11340, México
    Search for more papers by this author
  • Claudia Guadalupe Benítez-Cardoza,

    1. Laboratorio de Investigación Bioquímica, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México D.F. 07320, México
    Search for more papers by this author
  • Absalom Zamorano-Carrillo

    Corresponding author
    1. Laboratorio de Investigación Bioquímica, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México D.F. 07320, México
    • Guillermo Massieu Helguera #239 Fracc. “La Escalera,” Ticomán D.F.C.P. 07320 Mexico City, Mexico
    Search for more papers by this author

  • All the authors have contributed significantly to this work.

Abstract

Bax is a member of the Bcl-2 protein family that participates in mitochondrion-mediated apoptosis. In the early stages of the apoptotic pathway, this protein migrates from the cytosol to the outer mitochondrial membrane, where it is inserted and usually oligomerizes, making cytochrome c-compatible pores. Although several cellular and structural studies have been reported, a description of the stability of Bax at the molecular level remains elusive. This article reports molecular dynamics simulations of monomeric Bax at 300, 400, and 500 K, focusing on the most relevant structural changes and relating them to biological experimental results. Bax gradually loses its α-helices when it is submitted to high temperatures, yet it maintains its globular conformation. The resistance of Bax to adopt an extended conformation could be due to several interactions that were found to be responsible for maintaining the structural stability of this protein. Among these interactions, we found salt bridges, hydrophobic interactions, and hydrogen bonds. Remarkably, salt bridges were the most relevant to prevent the elongation of the structure. In addition, the analysis of our results suggests which conformational movements are implicated in the activation/oligomerization of Bax. This atomistic description might have important implications for understanding the functionality and stability of Bax in vitro as well as within the cellular environment.

Ancillary