Prime 2006

1
Prime 2006

• Lisa Danjing Zhao
• Progress Report 3
• July 28, 2006

2
Statement of Purpose

• To gain a better understanding of the structural
  properties in avian influenza binding properties
• Focus on host specificity, which sites
  hemagglutinin (HA) prefers to bind and other
  mutation hotspots
• Learn more about my Chinese culture and language.

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Progress Made

• Analyzed the 20 top binding ligands after Virtual
  Screening on 2FK0 (Influenza a virus (a/viet
  nam/1203/2004(h5n1)) was completed
• Reconfigured parameter files to output more
  conformations for it to be statistically
  significant
• Made the Grid box 40 x 40 x 40 rather than 60 x
  60 x 60 and performed docking on the top 20
  ligands with 20 conformations per ligand.
• Docking with a new program called DOCK6 (UCSF) to
  have a comparison with results from using
  AutoDockTools.
• DOCK6 allows us to dock with the ligand in both
  its rigid form and also in its flexible form
  (rotatable bonds)

4
Diversity Results
Left Top Binding Results Diversity 1865 Lowest
binding energy -11.12 kcal/mol Residue
Interactions Glu 190, Tyr 98, His 183 Right
Complex examined using Rasmol. Ligand (Red)
Hemagglutinin (Blue)
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3. Diversity 1100
2. Diversity 320 Val 135 is not in RBD
5. Diversity1864
4. Diversity 1986
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Progress (Cont.)

• Performed docking with 2FK0 (H5N1 Hemagglutinin)
  with
• a-2,3-linked sialic acid (Avian) Taken from 2DF3
  (The structure of Siglec-7 in complex with
  alpha(2,3)/alpha(2,6) disialyl lactotetraosyl
  2-(trimethylsilyl)ethyl)
• a-2,6-linked sialic acid (Human) Taken from 1PTO
  (The Structure of a Pertussis Toxin-Sugar Complex
  as a Model for Receptor Binding)
• Examined both results with ligplot to look at
  residue and hydrophobic interactions at the
  receptor binding domain

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Plans

• Perform docking again on 2FK0 (H5N1 avian
  hemagglutinin) with oligosaccharide (sialic acid,
  galactose, and NAG complex)
• Using only sialic acid alone did not give an
  accurate representation of the binding between HA
  and the host cell receptors.
• Dock with other subtypes of Avian Influenza
• In particular, H1, H2, and H3 are adapted to the
  human population
• Construct pharmacophore model of the H5N1
  receptor binding domain based on the results from
  virtual screening
• Pharmacophore is a specific, three dimensional
  map of biological properties common to all active
  conformations of a set of ligands which exhibit a
  particular activity. Conceptually, a
  pharmacophore is a distillation of the functional
  attributes of ligands which accomplish a specific
  task.
• Kavraki, E. (http//www.cnx.org/content/m11538/
  latest/)
• Complete Methods and Materials portion of
  research paper
• Software used AutoDockTools, Virtual Screening,
  Ligplot, Chimera, and DOCK6

8
Cultural Experiences
Summer Palace (July 22, 2006) Two of our
coworkers spent the day giving us a tour of
Summer Palace which was built in 1750, and
restored in 1886 after the war. The Summer Palace
is a luxurious Chinese garden, and is ranked as
of the greatest gardens of the world. UNESCO
listed it as one of the World Heritage Sites in
1998. "The natural landscape of hills and open
water is combined with artificial features such
as pavilions, halls, palaces, temples and bridges
to form a harmonious ensemble of outstanding
aesthetic value. http//whc.unesco.org
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References

• http//www.agnr.umd.edu/avianflu/
• Scripps Research Institute Molecular Graphics
  Laboratory

Acknowledgements

• Computer Network Information Center, Chinese
  Academy of Sciences
• Dr. Wilfred Li, National Biomedical Computation
  Resource
• Dr. Bill Chang, National Science Foundation