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Contribution of charged and polar residues for the formation of the E1–E2 heterodimer from Hepatitis C Virus

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Abstract

The transmembrane domains of the envelope glycoprotein E1 and E2 have crucial multifunctional roles in the biogenesis of hepatitis C virus. We have performed molecular dynamics simulations to investigate a structural model of the transmembrane segments of the E1–E2 heterodimer. The simulations support the key role of the Lys370–Asp728 ion pair for mediating the E1–E2 heterodimerization. In comparison to these two residues, the simulation results also reveal the differential effect of the conserved Arg730 residue that has been observed in experimental studies. Furthermore, we discovered the formation of inter-helical hydrogen bonds via Asn367 that stabilize dimer formation. Simulations of single and double mutants further demonstrate the importance of the ion-pair and polar interactions between the interacting helix monomers. The conformation of the E1 fragment in the simulation of the E1–E2 heterodimer is in close agreement with an NMR structure of the E1 transmembrane segment. The proposed model of the E1–E2 heterodimer supports the postulated cooperative insertion of both helices by the translocon complex into the bilayer.

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Acknowledgments

We are grateful for the financial support of the Universiti Teknologi MARA, Malaysia and by grant I 80469 by the Volkswagen foundation and for the research facilities from The Center for Bioinformatics Saarland University. We also thank the Deutsche Forschungsgemeinschaft Graduate School 1276/1 “Structure Formation and Transport in Complex Systems” for collaboration.

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Authors and Affiliations

  1. Center for Bioinformatics, Saarland University, 66041, Saarbruecken, Germany

    Siti Azma Jusoh & Volkhard Helms

  2. Faculty of Pharmacy, Universiti Technologi MARA, 40450, Shah Alam, Malaysia

    Siti Azma Jusoh

  3. Department of Internal Medicine I, Johann Wolfgang Goethe-University Hospital, 60590, Frankfurt am Main, Germany

    Christoph Welsch

  4. Computational Biology, Universität Erlangen-Nürnberg, BTE Gebäude, Erwin-Rommel-Str.3, 91058, Erlangen, Germany

    Shirley W. I. Siu & Rainer A. Böckmann

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Table S1

Average H-bonds analyzed for the data between 80 and 100 ns of MD simulations of E1–E2 wild-types and mutants. (PDF 11 kb)

Fig. S1

Results from secondary structure prediction programs. The consensus prediction is given at the bottom; the positions in the consensus sequence indicate that three or more methods gave the same results. Highlighted in blue in the consensus prediction are the charged residues Lys370, Asp728, and Arg730. The dotted lines show the segments which were used in the MD simulations. (PDF 22 kb)

Fig. S2

Final snapshot after 100 ns of MD simulations of the H-segment monomers containing a charged residue in the middle of their TM domains: (a) H-segment with charged Lys370 and (b) H-segment with charged Asp728. Lipid tails and ions are not shown for clarity. (PDF 50 kb)

Fig. S3

Root-mean-square deviations (RMSDs) of E1 and E2 TM domains of the E1–E2 wild-type and mutant heterodimers. (A) RMSDs of wild-type E1–E2 heterodimers versus the E1 and E2 simulations of isolated helices. (B) RMSDs of single mutants which contain a salt-bridge at the helix-helix packing interface and (C) RMSDs of double mutants. In (B) and (C), the E1–E2 wild-type 1 is shown for comparison. (PDF 137 kb)

Fig. S4

Final snapshots after 100 ns MD simulation of the E1–E2 heterodimers in the two wild-type simulations. The conserved residues Asn367, Lys370, Asp728, and Arg730 are highlighted as stick presentation. Lipid tails and ions are not shown for clarity. (PDF 305 kb)

Fig. S5

Final snapshot of mutants (a) K370A and (b) D728A. The conserved residues Asn367, Lys370, Asp728, and Arg730 are shown as stick representation. The mutated residues, lipid bilayer, water and ions molecules are not shown for clarity. (PDF 43 kb)

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Jusoh, S.A., Welsch, C., Siu, S.W.I. et al. Contribution of charged and polar residues for the formation of the E1–E2 heterodimer from Hepatitis C Virus. J Mol Model 16, 1625–1637 (2010). https://doi.org/10.1007/s00894-010-0672-1

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