molecular dynamics of the avian influenza virus team members: ashvin srivatsa, michael fu, ellen...
TRANSCRIPT
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Molecular Dynamics of the Avian Influenza Virus
Team Members: Ashvin Srivatsa, Michael Fu, Ellen Chuang, Ravi Sheth
Team Leader: Yuan Zhang
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Contents
• Influenza Background• How Influenza Works• Molecular Dynamics• Objective• Procedure• Results• Conclusion
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Influenza Background
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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
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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.
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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
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How Influenza Works
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Structure of Bird Flu Virus
• Protein Coat– Hemagglutinin – bonds
virus to cell membrane– Neuraminidase – helps
virus reproduce in cell
• Lipid Membrane• RNA
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Lifecycle of Bird Flu Virus
• Enters and infects cell
• Reproduce genetic material
• Cell lyses, releasing new viruses
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Fusion Peptide
• Part of Hemagglutinin protein• Binds virus to cell membrane
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Molecular Dynamics
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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
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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
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A silicon nanopore, rendered with VMD by the Theoretical and Computational Biophysics Group at
the University of Illinois at Urbana-Champaign
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Objective
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Objective1. Utilize VMD and NAMD2 to conduct
simulations of the influenza fusion peptide being inserted into a lipid membrane on OSC’s supercomputer clusters
2. Determine how various mutations of the fusion peptide affects its ability to penetrate a lipid membrane
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Procedure
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Procedure
1. Acquire protein structure files (.pdb) – pdb.org
2. Generate lipid membrane, position protein on membrane
3. Solvate (immerse in water) the protein4. Create batch files that tell supercomputer
what to do
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Procedure (Cont.)
5. Perform an equilibration simulation to equilibrate protein
6. Execute simulation that pulls protein into membrane
7. Produce visualization
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Results
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Fusion Peptide Equilibration (H1N1)
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Fusion Peptide Pulling (H1N1)
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Fusion Peptide Pulling #2 (H1N1)
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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
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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
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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)
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G1V(green), G1S (red) mutants, H1N1 (orange)
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G1V(green), G1S (red) mutants, H1N1 (orange)
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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”
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Mutation 2
• Mutation near bend in peptide• W14A / H3N2• Boomerang structure is critical to peptide (Lai,
Park, White, Tamm)
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W14A(green), H1N1 (blue)
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W14A(green), H1N1 (blue)
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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
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Mutation 3
• N12G• Affects Boomerang Structure• Chosen by team members (not previously
attempted)
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N12G(orange), H1N1 (blue)
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N12G(orange), H1N1 (blue)
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Analysis
• N12G bunches up halfway through• Does not insert as much as H1N1• Further proves that proper bend is essential
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Conclusion
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Conclusions
• Boomerang structure of the fusion peptide is essential for proper insertion
• Glycine is essential in the “head” position of the fusion peptide
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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
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Acknowledgements
Yuan Zhang(project leader)
Barbara Woodall(UNIX)
Elaine Pritchard(Organization)
Brianna, Daniel(Dorm Supervisors)
SI SponsorsParents
VMD(University of Illinois)
NAMD2(University of Illinois)
ClustalW(Amino Acid Alignment)
OSC(Supercomputing Time)
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Questions?