QM/MM Free Energy Calculations of IRE1 Reveal a Unique Protonation State of the Catalytic Lys599.

ABSTRACT: Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease identified as therapeutic target in multiple diseases. Inspired by the recent work on the assessment of lysine and cysteine reactivities, we present a simple and intuitive protocol for the assessment of reactive lysine, while characterizing a unique protonation state of Lys599 located in the kinase domain. Using Quantum Mechanics/Molecular Mechanics (QM/MM) calculations, QM/MM well-tempered metadynamics simulations (QM/MM WT-MetaD), and classical Molecular Dynamics (MD), we have investigated inhibitor binding in three different states of the IRE1 kinase: (i) DFG-in/αC-in (DICI) conformation; (ii) the DFG-out/αC-out (DOCO) conformation, and (iii) the DFG-in/αC-out (DICO) conformation. Our findi

SUBMITTER: Carlesso A 

PROVIDER: S-EPMC12678879 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature