Computational studies of lipopolysaccharide interactions with membrane transporters
<p>Lipopolysaccharide (LPS) lipids compose the outer leaflet of the outer membrane in pathogenic Gram-negative bacteria and are chiefly responsible for host-immune responses. Therefore, the membrane proteins which interact with LPS as well as the transport system for LPS, the Lpt system, repre...
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| Formaat: | Thesis |
| Taal: | English |
| Gepubliceerd in: |
2022
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| _version_ | 1826309446912966656 |
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| author | Sauer, J |
| author2 | Stansfeld, P |
| author_facet | Stansfeld, P Sauer, J |
| author_sort | Sauer, J |
| collection | OXFORD |
| description | <p>Lipopolysaccharide (LPS) lipids compose the outer leaflet of the outer membrane in pathogenic Gram-negative bacteria and are chiefly responsible for host-immune responses. Therefore, the membrane proteins which interact with LPS as well as the transport system for LPS, the Lpt system, represents a class of extremely important drug targets. The focus of this thesis is to employ molecular dynamics studies to examine the effects of LPS binding upon the Lpt complex at every stage of the transportation process, validating and conferring recent mass spectrometry and cryo-electron microscopy (Cryo-EM) studies.</p>
<p>Molecular dynamics (MD) studies in this thesis reveal that LPS binds to other proteins found in the inner membrane in a similar manner to the transporter subcomplex LptB2FGC. Within the transporter itself, simulations of recently resolved Cryo-EM structure reveal that LPS shifts position to facilitate transportation across the periplasmic protein bridging complex. Binding energy calculations between the acyl chains of LPS and the bridging complex reveal a generally flat energetic landscape before reaching the terminal outer membrane subcomplex of the Lpt system, LptDE. Here, MD studies validate and explain hydrogen-deuterium exchange mass spectrometry results which capture the conformational changes required for LPS insertion into the outer membrane. With an increasing prevalence of antibiotic resistant pathogens, this thesis concerns characterising LPS interactions with its transport machinery suggesting means for developing antimicrobial therapeutics which target this essential system.</p> |
| first_indexed | 2024-03-07T07:35:50Z |
| format | Thesis |
| id | oxford-uuid:06cf50d1-c83c-44da-97a6-844674f27a2e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:35:50Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:06cf50d1-c83c-44da-97a6-844674f27a2e2023-03-09T10:31:59ZComputational studies of lipopolysaccharide interactions with membrane transportersThesishttp://purl.org/coar/resource_type/c_db06uuid:06cf50d1-c83c-44da-97a6-844674f27a2eStructural biologyNative mass spectrometryMolecular dynamicsHydrogen deuterium exchangeHDXEnglishHyrax Deposit2022Sauer, JStansfeld, PVivien Robinson, C<p>Lipopolysaccharide (LPS) lipids compose the outer leaflet of the outer membrane in pathogenic Gram-negative bacteria and are chiefly responsible for host-immune responses. Therefore, the membrane proteins which interact with LPS as well as the transport system for LPS, the Lpt system, represents a class of extremely important drug targets. The focus of this thesis is to employ molecular dynamics studies to examine the effects of LPS binding upon the Lpt complex at every stage of the transportation process, validating and conferring recent mass spectrometry and cryo-electron microscopy (Cryo-EM) studies.</p> <p>Molecular dynamics (MD) studies in this thesis reveal that LPS binds to other proteins found in the inner membrane in a similar manner to the transporter subcomplex LptB2FGC. Within the transporter itself, simulations of recently resolved Cryo-EM structure reveal that LPS shifts position to facilitate transportation across the periplasmic protein bridging complex. Binding energy calculations between the acyl chains of LPS and the bridging complex reveal a generally flat energetic landscape before reaching the terminal outer membrane subcomplex of the Lpt system, LptDE. Here, MD studies validate and explain hydrogen-deuterium exchange mass spectrometry results which capture the conformational changes required for LPS insertion into the outer membrane. With an increasing prevalence of antibiotic resistant pathogens, this thesis concerns characterising LPS interactions with its transport machinery suggesting means for developing antimicrobial therapeutics which target this essential system.</p> |
| spellingShingle | Structural biology Native mass spectrometry Molecular dynamics Hydrogen deuterium exchange HDX Sauer, J Computational studies of lipopolysaccharide interactions with membrane transporters |
| title | Computational studies of lipopolysaccharide interactions with membrane transporters |
| title_full | Computational studies of lipopolysaccharide interactions with membrane transporters |
| title_fullStr | Computational studies of lipopolysaccharide interactions with membrane transporters |
| title_full_unstemmed | Computational studies of lipopolysaccharide interactions with membrane transporters |
| title_short | Computational studies of lipopolysaccharide interactions with membrane transporters |
| title_sort | computational studies of lipopolysaccharide interactions with membrane transporters |
| topic | Structural biology Native mass spectrometry Molecular dynamics Hydrogen deuterium exchange HDX |
| work_keys_str_mv | AT sauerj computationalstudiesoflipopolysaccharideinteractionswithmembranetransporters |