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Dostęp zamkniętyVarying molecular interactions explain aspects of crowder-dependent enzyme function of a viral protease
| dc.abstract.en | Biochemical processes in cells, including enzyme-catalyzed reactions, occur in crowded conditions with various background macromolecules occupying up to 40% of cytoplasm’s volume. Viral enzymes in the host cell also encounter such crowded conditions as they often function at the endoplasmic reticulum membranes. We focus on an enzyme encoded by the hepatitis C virus, the NS3/4A protease, which is crucial for viral replication. We have previously found experimentally that synthetic crowders, polyethylene glycol (PEG) and branched polysucrose (Ficoll), differently affect the kinetic parameters of peptide hydrolysis catalyzed by NS3/4A. To gain understanding of the reasons for such behavior, we perform atomistic molecular dynamics simulations of NS3/4A in the presence of either PEG or Ficoll crowders and with and without the peptide substrates. We find that both crowder types make nanosecond long contacts with the protease and slow down its diffusion. However, they also affect the enzyme structural dynamics; crowders induce functionally relevant helical structures in the disordered parts of the protease cofactor, NS4A, with the PEG effect being more pronounced. Overall, PEG interactions with NS3/4A are slightly stronger but Ficoll forms more hydrogen bonds with NS3. The crowders also interact with substrates; we find that the substrate diffusion is reduced much more in the presence of PEG than Ficoll. However, contrary to NS3, the substrate interacts more strongly with Ficoll than with PEG crowders, with the substrate diffusion being similar to crowder diffusion. Importantly, crowders also affect the substrate-enzyme interactions. We observe that both PEG and Ficoll enhance the presence of substrates near the active site, especially near catalytic H57 but Ficoll crowders increase substrate binding more than PEG molecules. |
| dc.affiliation | Uniwersytet Warszawski |
| dc.contributor.author | Ostrowska, Natalia |
| dc.contributor.author | Trylska, Joanna |
| dc.contributor.author | Feig, Michael |
| dc.date.accessioned | 2024-01-26T11:45:48Z |
| dc.date.available | 2024-01-26T11:45:48Z |
| dc.date.issued | 2023 |
| dc.description.finance | Publikacja bezkosztowa |
| dc.description.number | 4 |
| dc.description.volume | 19 |
| dc.identifier.doi | 10.1371/JOURNAL.PCBI.1011054 |
| dc.identifier.issn | 1553-734X |
| dc.identifier.uri | https://repozytorium.uw.edu.pl//handle/item/124559 |
| dc.identifier.weblink | https://dx.plos.org/10.1371/journal.pcbi.1011054 |
| dc.language | eng |
| dc.pbn.affiliation | biological sciences |
| dc.relation.ispartof | PLoS Computational Biology |
| dc.relation.pages | e1011054 |
| dc.rights | ClosedAccess |
| dc.sciencecloud | nosend |
| dc.title | Varying molecular interactions explain aspects of crowder-dependent enzyme function of a viral protease |
| dc.type | JournalArticle |
| dspace.entity.type | Publication |