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Molecular Dynamics of the Avian Influenza Virus

Molecular Dynamics of the Avian Influenza Virus. Team Members: Ashvin Srivatsa , Michael Fu, Ellen Chuang, Ravi Sheth Team Leader: Yuan Zhang. Contents. Influenza Background How Influenza Works Molecular Dynamics Objective Procedure Results Conclusion. Influenza Background.

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Molecular Dynamics of the Avian Influenza Virus

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  1. Molecular Dynamics of the Avian Influenza Virus Team Members:AshvinSrivatsa, Michael Fu, Ellen Chuang, Ravi Sheth Team Leader: Yuan Zhang

  2. Contents • Influenza Background • How Influenza Works • Molecular Dynamics • Objective • Procedure • Results • Conclusion

  3. Influenza Background

  4. The Influenza Problem • “Flu” • Common viral infection of lungs • Many different strains which mutate regularly • Different levels of virulence • Kills roughly half a million people per year

  5. Historical Flu Pandemics • 1918 Spanish Flu (H1N1) • 500,000 deaths in U.S. • 1957 Asian Flu (H2N2) • 69,800 deaths in U.S. • 1968 Hong Kong Flu (H3N2) • 33,800 deaths in U.S.

  6. Avian Influenza • H5N1 • Form of Influenza A Virus • One of the most virulent strains today, spreads only from birds to humans • Similar to human “common flu” • Mutates frequently, makes it hard to develop countermeasures • If a mutation allows for it to spread from human to human, pandemic would follow

  7. How Influenza Works

  8. Structure of Bird Flu Virus • Protein Coat • Hemagglutinin – bonds virus to cell membrane • Neuraminidase – helps virus reproduce in cell • Lipid Membrane • RNA

  9. Lifecycle of Bird Flu Virus • Enters and infects cell • Reproduce genetic material • Cell lyses, releasing new viruses

  10. Fusion Peptide • Part of Hemagglutinin protein • Binds virus to cell membrane

  11. Molecular Dynamics

  12. Molecular Dynamics (MD) • Involves study of computer simulations that allow molecules and atoms to interact • Extremely complex, based on physics laws • Must be run on powerful supercomputers

  13. MD Software • Many different types of software solutions exist • We utilized VMD and NAMD • VMD – Visual Molecular Dynamics • NAMD2 – Not (just) Another Molecular Dynamics program

  14. A silicon nanopore, rendered with VMD by the Theoretical and Computational Biophysics Group at the University of Illinois at Urbana-Champaign

  15. Objective

  16. Objective • Utilize VMD and NAMD2 to conduct simulations of the influenza fusion peptide being inserted into a lipid membrane on OSC’s supercomputer clusters • Determine how various mutations of the fusion peptide affects its ability to penetrate a lipid membrane

  17. Procedure

  18. Procedure • Acquire protein structure files (.pdb) – pdb.org • Generate lipid membrane, position protein on membrane • Solvate (immerse in water) the protein • Create batch files that tell supercomputer what to do

  19. Procedure (Cont.) • Perform an equilibration simulation to equilibrate protein • Execute simulation that pulls protein into membrane • Produce visualization

  20. Results

  21. Fusion Peptide Equilibration (H1N1)

  22. Fusion Peptide Pulling (H1N1)

  23. Fusion Peptide Pulling #2 (H1N1)

  24. Next Step: Mutations • Random change in genetic material • Changes amino acid structure in proteins • New strains of influenza arise through random mutations as well as through natural selection

  25. Comparison of Amino Sequences • Different Strains of the 20 amino acid fusion peptide • Mutation Names – based on original amino acid, position, and new amino acid

  26. Mutation 1 • Mutation at the “head” of the protein • Variants G1V, G1S • (Changes to Valine, Serine) • Changes way each peptide enters the membrane (Li, Han, Lai, Bushweller, Cafisso, Tamm)

  27. G1V(green), G1S (red) mutants, H1N1 (orange)

  28. G1V(green), G1S (red) mutants, H1N1 (orange)

  29. Analysis • The H1N1 maintains a straight structure • G1V, G1S variants bunch up – reduce efficiency • Shows that the Glycine is important amino acid on the “head”

  30. Mutation 2 • Mutation near bend in peptide • W14A / H3N2 • Boomerang structure is critical to peptide (Lai, Park, White, Tamm)

  31. W14A(green), H1N1 (blue)

  32. W14A(green), H1N1 (blue)

  33. Analysis • W14A bunches up, after going in half way, comes back out • H1N1 maintains structure • Shows that “boomerang” or bend is essential • Also could have contributed the success of the 1918 H1N1 outbreak, compared to H3N2

  34. Mutation 3 • N12G • Affects Boomerang Structure • Chosen by team members (not previously attempted)

  35. N12G(orange), H1N1 (blue)

  36. N12G(orange), H1N1 (blue)

  37. Analysis • N12G bunches up halfway through • Does not insert as much as H1N1 • Further proves that proper bend is essential

  38. Conclusion

  39. Conclusions • Boomerang structure of the fusion peptide is essential for proper insertion • Glycine is essential in the “head” position of the fusion peptide

  40. The Bigger Picture • The fusion peptide process is a target for drug intervention • Influenza mutates quickly • Deadly implications if H5N1 mutates to spread from human to human • Further research is essential to protect humans from another pandemic

  41. Acknowledgements Yuan Zhang (project leader) Barbara Woodall (UNIX) Elaine Pritchard (Organization) Brianna, Daniel (Dorm Supervisors) SI Sponsors Parents VMD (University of Illinois) NAMD2 (University of Illinois) ClustalW (Amino Acid Alignment) OSC (Supercomputing Time)

  42. Questions?

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