Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation.
Premila P Samuel RussellAndrew K MaytinMeredith M RickardMatthew C RussellTaras V PogorelovMartin GruebelePublished in: The journal of physical chemistry letters (2024)
Many enzymes undergo major conformational changes to function in cells, particularly when they bind to more than one substrate. We quantify the large-amplitude hinge-bending landscape of human phosphoglycerate kinase (PGK) in a human cytoplasm. Approximately 70 μs of all-atom simulations, upon coarse graining, reveal three metastable states of PGK with different hinge angle distributions and additional substates. The "open" state was more populated than the "semi-open" or "closed" states. In addition to free energies and barriers within the landscape, we characterized the average transition state passage time of ≈0.3 μs and reversible substrate and product binding. Human PGK in a dilute solution simulation shows a transition directly from the open to closed states, in agreement with previous SAXS experiments, suggesting that the cell-like model environment promotes stability of the human PGK semi-open state. Yeast PGK also sampled three metastable states within the cytoplasm model, with the closed state favored in our simulation.
Keyphrases
- endothelial cells
- minimally invasive
- molecular dynamics
- single cell
- induced pluripotent stem cells
- molecular dynamics simulations
- pluripotent stem cells
- gene expression
- induced apoptosis
- mesenchymal stem cells
- high resolution
- endoplasmic reticulum stress
- transcription factor
- cell death
- oxidative stress
- signaling pathway
- density functional theory
- dna methylation
- functional connectivity
- bone marrow
- resting state
- pi k akt
- dna binding