ArticleComputational and structural biotechnology journal2025
Characterization of the KRas G12D-inhibitor interactions by differential HDX-MS and molecular dynamics simulations.
Article in Computational and structural biotechnology journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- A Hit Prioritization Strategy for Compound Library Screening Using LiP-MS and Molecular Dynamics Simulations Applied to KRas G12D Inhibitors.Analytical chemistry · 2025Article
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Authors and funding
7 authors.
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Abstract
Hydrogen-deuterium exchange (HDX) combined with mass spectrometry (MS) is a powerful technique for studying changes in protein structure and dynamics upon ligand binding. Protein-ligand complexes can result in increased protection of peptide-bond amides in HDX indicating protein structure stabilization. We have characterized the interaction of small-molecule inhibitors towards the KRas G12D oncoprotein by intact-protein and bottom-up HDX-MS, in combination with molecular dynamics (MD) simulations. Significant differences in HDX protection were detected upon inhibitor binding in the flexible switch-II pocket of the protein. MD simulations of the free and inhibitor-bound KRas G12D proteins also revealed changes in the hydrogen bond network of backbone amides in the switch-II region upon inhibitor binding, explaining the observed HDX protection changes. We have proposed simple semi-empirical metrics which relate changes in HDX-MS experimental values and observed in MD simulations changes in individual backbone hydrogen-bonds between free- and ligand-bound protein states. This combined HDX-MS and MD approach provides an atomistic picture of changes in the KRas G12D secondary structure upon ligand binding and may be a useful tool for future drug design efforts.
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