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QM/MM Well-Tempered Metadynamics Study of the Mechanism of XBP1 mRNA Cleavage by Inositol Requiring Enzyme 1α RNase.
Mahdizadeh, Sayyed Jalil; Pålsson, Emil; Carlesso, Antonio; Chevet, Eric; Eriksson, Leif A.
Afiliação
  • Mahdizadeh SJ; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
  • Pålsson E; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
  • Carlesso A; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
  • Chevet E; Faculty of Biomedical Sciences, Euler Institute, Università della Svizzera Italiana (USI),, Lugano 6904, Switzerland.
  • Eriksson LA; Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, 405 30 Göteborg, Sweden.
J Chem Inf Model ; 62(17): 4247-4260, 2022 09 12.
Article em En | MEDLINE | ID: mdl-35960929
A range of in silico methodologies were herein employed to study the unconventional XBP1 mRNA cleavage mechanism performed by the unfolded protein response (UPR) mediator Inositol Requiring Enzyme 1α (IRE1). Using Protein-RNA molecular docking along with a series of extensive restrained/unrestrained atomistic molecular dynamics (MD) simulations, the dynamical behavior of the system was evaluated and a reliable model of the IRE1/XBP1 mRNA complex was constructed. From a series of well-converged quantum mechanics molecular mechanics well-tempered metadynamics (QM/MM WT-MetaD) simulations using the Grimme dispersion interaction corrected semiempirical parametrization method 6 level of theory (PM6-D3) and the AMBER14SB-OL3 force field, the free energy profile of the cleavage mechanism was determined, along with intermediates and transition state structures. The results show two distinct reaction paths based on general acid-general base type mechanisms, with different activation energies that perfectly match observations from experimental mutagenesis data. The study brings unique atomistic insights into the cleavage mechanism of XBP1 mRNA by IRE1 and clarifies the roles of the catalytic residues H910 and Y892. Increased understanding of the details in UPR signaling can assist in the development of new therapeutic agents for its modulation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleases / Inositol Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleases / Inositol Idioma: En Ano de publicação: 2022 Tipo de documento: Article