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Weak Selectivity Predicted for Modeled Bundles of Viral Channel-Forming Protein E5 of Human Papillomavirus-16
Dhani Ram Mahato1, Wolfgang B Fischer1
1Institute of Biophotonics and Biophotonics & Molecular Imaging Research Center (BMIRC), School of Biomedical Science and Engineering, National Yang-Ming University , Taipei 112, Taiwan.
Abstract:
Protein E5 is a polytopic 83 amino acid membrane protein with three transmembrane domains (TMDs), encoded by high-risk human papillomavirus-16 (HPV-16). HPV-16 is found to be the causative agent for cervical cancer. Protein E5, among other proteins (e.g., E6, E7), is expressed at an "early" (E) stage when the cell turns malignant. It has been experimentally found that E5 forms hexameric assemblies, which show the characteristics of the class of so-called channel-forming proteins by rendering lipid membranes permeable to ions and small molecules. Protein E5 is used to achieve structural models of the protein in assembled bundles using a force field-based docking approach. Extended molecular dynamics simulations of selected bundles in fully hydrated lipid bilayers suggest the second TMD to be pore-lining, allowing for water columns to exist within the lumen of the pore. Full correlation analysis indicates asymmetric dynamics within the monomers of the bundle. Potential of mean force calculations of a snapshot structure of the putative open pore of the protein bundle propose low selectivity.
Insights
Human papillomavirus-16 (HPV-16) E5 protein forms hexameric channels, increasing membrane permeability. Molecular dynamics simulations reveal its second transmembrane domain lines the pore, suggesting low ion selectivity.
Area of Science:
- Structural biology
- Membrane protein biophysics
- Oncogenic viral proteins
Background:
- Protein E5, encoded by high-risk human papillomavirus-16 (HPV-16), is an 83-amino acid polytopic membrane protein.
- HPV-16 is a primary cause of cervical cancer, with E5 protein expression occurring during early stages of cellular malignancy.
- Experimentally, E5 forms hexameric assemblies that render lipid membranes permeable to ions and small molecules, characteristic of channel-forming proteins.
Purpose of the Study:
- To develop structural models of assembled HPV-16 E5 protein bundles.
- To investigate the pore-lining regions and dynamics of E5 hexamers within lipid bilayers.
- To assess the ion selectivity of the putative E5 protein pore.
Main Methods:
- Force field-based docking approach to generate structural models of E5 hexameric assemblies.
- Extended molecular dynamics simulations of E5 bundles in hydrated lipid bilayers.
- Full correlation analysis and potential of mean force calculations.
Main Results:
- Structural models suggest the second transmembrane domain (TMD) is pore-lining, facilitating water columns within the pore lumen.
- Asymmetric dynamics were observed within the monomers comprising the E5 hexameric bundle.
- Potential of mean force calculations indicate low selectivity of the putative open pore for ions.
Conclusions:
- The HPV-16 E5 protein forms ion-permeable channels through hexameric assembly, with the second TMD playing a crucial role in pore formation.
- The observed asymmetric dynamics and low ion selectivity provide insights into the functional mechanism of this viral oncoprotein.
- These findings contribute to understanding the molecular basis of HPV-induced cervical carcinogenesis.
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