Elucidating the Structural and Dynamical Properties of the Intrinsically Disordered Protein Nrf2 Using Molecular Dynamics Simulations
Abstract
The nuclear factor erythroid 2-related factor 2 (Nrf2) protein is a critical transcription factor for activating the antioxidant response pathway, a primary defense mechanism against disproportionate levels of oxidants in the cell, via the upregulation of cytoprotective genes. Notably, aberrant activation of Nrf2 in cancer cells increases their resistance to chemotherapy, rendering the treatment ineffective. The focus was to uncover the conformational landscape of Nrf2’s Neh4 and Neh5 domains, which participate in crucial interactions for complete transcriptional activation. Since Nrf2 is an intrinsically disordered protein (IDP), molecular dynamics simulations were employed to capture its dynamic nature and conformational heterogeneity. The Neh4 and Neh5 domains differed in their structural propensities, where the phosphorylation of Neh5’s S193 residue had little effect. This work points to the domains having potentially different binding mechanisms. In addition, performance discrepancies between force fields CHARMM36m and Amber99SB*-ILDNP were identified, potentially contributing to future force field development.