Abstract
Envelope glycoproteins of Hepatitis C Virus (HCV) play an important role in the virus assembly and initial entry into host cells. Conserved charged residues of the E2 transmembrane (TM) domain were shown to be responsible for the heterodimerization with envelope glycoprotein E1. Despite intensive research on both envelope glycoproteins, the structural information is still not fully understood. Recent findings have revealed that the stem (ST) region of E2 also functions in the initial stage of the viral life cycle. We have previously shown the effect of the conserved charged residues on the TM helix monomer of E2. Here, we extended the model of the TM domain by adding the adjacent ST segment. Explicit molecular dynamics simulations were performed for the E2 amphiphilic segment of the ST region connected to the putative TM domain (residues 683-746). Structural conformation and behavior are studied and compared with the nuclear magnetic resonance (NMR)-derived segment of E2 ( 2KQZ.pdb ). We observed that the central helix of the ST region (residues 689 - 703) remained stable as a helix in-plane to the lipid bilayer. Furthermore, the TM domain appeared to provide minimal contribution to the structural stability of the amphipathic region. This study also provides insight into the orientation and positional preferences of the ST segment with respect to the membrane lipid-water interface.
Highlights
Envelope glycoproteins E1 and E2 are essential for the initial binding and internalization of Hepatitis C Virus (HCV) into host cells
The ion-pair interaction of the E1–E2 heterodimer was captured in the molecular dynamic (MD) simulation studies based on the model that placed the charged Asp and Lys at the helix-helix interface[4,5]
Consistent results were shown from circular dichroism (CD) spectra and nuclear magnetic resonance (NMR) with 50% 2,2,2-trifluoroethanol (TFE) environment, which both detected the presence of helical segments in the E2-ST region
Summary
Envelope glycoproteins E1 and E2 are essential for the initial binding and internalization of Hepatitis C Virus (HCV) into host cells. Both glycoproteins have been shown to interact as a non-covalent heterodimer during biosynthesis[1]. The main contribution of Asp was postulated to be located at the helix-helix interface and involved the formation of a salt bridge with the Lys of the E1 envelope glycoprotein[2]. The ion-pair interaction of the E1–E2 heterodimer was captured in the molecular dynamic (MD) simulation studies based on the model that placed the charged Asp and Lys at the helix-helix interface[4,5]
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