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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
Contents
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Influenza Background
How Influenza Works
Molecular Dynamics
Objective
Procedure
Results
Conclusion
Influenza Background
The Influenza Problem
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“Flu”
Common viral infection of lungs
Many different strains which mutate regularly
Different levels of virulence
Kills roughly half a million people per year
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.
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
How Influenza Works
Structure of Bird Flu Virus
• Protein Coat
– Hemagglutinin –
bonds virus to cell
membrane
– Neuraminidase – helps
virus reproduce in cell
• Lipid Membrane
• RNA
Lifecycle of Bird Flu Virus
• Enters and
infects cell
• Reproduce
genetic material
• Cell lyses,
releasing new
viruses
Fusion Peptide
• Part of Hemagglutinin protein
• Binds virus to cell membrane
Molecular Dynamics
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
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
A silicon nanopore, rendered with VMD by the
Theoretical and Computational Biophysics Group at
the University of Illinois at Urbana-Champaign
Objective
Objective
1. 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
Procedure
Procedure
1. Acquire protein structure files (.pdb) –
pdb.org
2. Generate lipid membrane, position protein
on membrane
3. Solvate (immerse in water) the protein
4. Create batch files that tell supercomputer
what to do
Procedure (Cont.)
5. Perform an equilibration simulation to
equilibrate protein
6. Execute simulation that pulls protein into
membrane
7. Produce visualization
Results
Fusion Peptide Equilibration (H1N1)
Fusion Peptide Pulling (H1N1)
Fusion Peptide Pulling #2 (H1N1)
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
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
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)
G1V(green), G1S (red) mutants, H1N1 (orange)
G1V(green), G1S (red) mutants, H1N1 (orange)
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”
Mutation 2
• Mutation near bend in peptide
• W14A / H3N2
• Boomerang structure is critical to peptide (Lai,
Park, White, Tamm)
W14A(green), H1N1 (blue)
W14A(green), H1N1 (blue)
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
Mutation 3
• N12G
• Affects Boomerang Structure
• Chosen by team members (not previously
attempted)
N12G(orange), H1N1 (blue)
N12G(orange), H1N1 (blue)
Analysis
• N12G bunches up halfway through
• Does not insert as much as H1N1
• Further proves that proper bend is essential
Conclusion
Conclusions
• Boomerang structure of the fusion peptide is
essential for proper insertion
• Glycine is essential in the “head” position of
the fusion peptide
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
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)
Questions?