Journal
ACS OMEGA
Volume 7, Issue 34, Pages 29587-29597Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.2c01289
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Funding
- NIH [R15 GM128102-01]
- NSF [CNS-0959856, CNS-095985]
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Using molecular dynamics simulations, this study explores the conformational and energetic landscape of GPX4 protein and its mutant variants, aiming to identify the allosteric networks of the enzyme. The findings provide insights into the enzyme's mechanism and have implications for drug design efforts.
Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, effectively inhibiting iron-dependent cell death or ferroptosis. The upregulation of the enzyme by the mutations at residues D21 and D23 has been suggested to be associated with higher protein activity, which confers more protection against neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Therefore, it has become an attractive target for treating and preventing neurodegenerative diseases. However, identifying means of mimicking the beneficial effects of these mutations distant from the active site constitutes a formidable challenge in moving toward therapeutics. In this study, we explore using molecular dynamics simulations to computationally map the conformational and energetic landscape of the wild-type GPX4 protein and three mutant variants to identify the allosteric networks of the enzyme. We present the conformational dynamic profile providing the desired signature behavior of the enzyme. We also discuss the implications of these findings for drug design efforts.
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