Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, which effectively inhibits iron-dependent cell death, or ferroptosis. This property makes GPX4 an interesting target for pharmaceutical intervention, since upregulation of the enzyme could provide a new approach to ferroptosis-related neurodegenerative pathology such as Alzeimer's, Parkinson's, and Huntington's diseases. Here we report computational modeling studies on upregulating GPX4 based on the allosteric effect. GPX4 is globular protein with multiple substates and lacks deep druggable pockets, which makes identifying allosteric sites by inspection difficult. In this study, Markov State Models from molecular dynamics simulations (MD-MSMs) are used to map the conformational energy landscapes for the wild-type GPX4 and the mutant variants D21A, D23A, and the double mutant, which are distal to the active site and known to influence functional activity. Conformational substates are obtained from the MD trajectories using Markov State Models and form a basis for elucidating putative allosteric networks and predicting druggable allosteric sites on the enzyme. The results indicate distinct conformational substates in the energy landscape corresponding to the mutated landscape, which we associate with activation of the enzyme. Coupled with lead residues identified from MD sector analysis that are also located on the surface of the protein, we propose sites for development of therapeutic allosteric effectors.
"},{"label":"Degree","value":["Bachelor of Arts with Departmental Honors"]},{"label":"Author-supplied Keywords","value":["Allostery","Molecular dynamics","Markov state model"]},{"label":"Administrative Note","value":"Drupal Node ID: 24251