Transcript Application to understanding HIV disease

Modelling proteomes:
Application to understanding HIV disease progression
Ram Samudrala
Department of Microbiology
University of Washington
How does the genome of an organism
specify its behaviour
and characteristics?
Proteome – all proteins of a particular system
~60,000 in human
~4500 in bacteria
like Salmonella and
E. coli
15 in HIV
Several thousand
distinct sequence
families
Modelling proteomes – understand the structure of individual proteins
A few thousand
distinct structural
folds
Modelling proteomes – understand their individual functions
Thousands of
possible functions
Modelling proteomes – understand their expression
Different expression
patterns based on
time and location
Modelling proteomes – understand their interactions
Interactions and
expression patterns
are interdependent
with structure and
function
CASP6 prediction (model1) for T0215
5.0 Å Cα RMSD for all 53 residues
Ling-Hong Hung/Shing-Chung Ngan
CASP6 prediction (model1) for T0281
4.3 Å Cα RMSD for all 70 residues
Ling-Hong Hung/Shing-Chung Ngan
CASP6 prediction (model1) for T0231
1.3 Å Cα RMSD for all 137 residues (80% ID)
Tianyun Liu
CASP6 prediction (model1) for T0271
2.4 Å Cα RMSD for all 142 residues (46% ID)
Tianyun Liu
Similar global sequence or structure does not imply similar function
TIM barrel
proteins
2246 with
known structure
hydrolase
ligase
lyase
oxidoreductase
transferase
Function prediction from structure
Kai Wang
Prediction of protein interaction networks
Target proteome
Interacting protein database
85%
protein a
experimentally
determined
interaction
protein A
predicted
interaction
protein B
protein b
90%
Assign confidence based on similarity and strength of interaction
Key paradigm is the use of homology to transfer information
across organisms; not limited to yeast, fly, and worm
Consensus of interactions helps with confidence assignments
Jason McDermott
E. coli predicted protein interaction network
Jason McDermott
H. sapiens predicted protein interaction network
Jason McDermott
Identification of virulence factors
Jason McDermott
Bioverse – explore relationships among molecules and systems
http://bioverse.compbio.washington.edu
Jason McDermott/Michal Guerquin/Zach Frazier
Prediction of HIV-1 protease-inhibitor binding energies with MD
Jenwitheesuk E, Samudrala R. Antiviral Therapy 10: 157-166, 2005.
Jenwitheesuk E, Samudrala R. BMC Structural Biology 3: 2, 2003.
Ekachai Jenwitheesuk
Experiment
Prediction of HIV-1 protease IC50 values with linear regression
Prediction
Wang K, Samudrala R, Mittler J. Journal of Infectious Diseases 190: 2055-2056, 2004.
Wang K, Samudrala R, Mittler J. Antiviral Therapy 9: 703-712, 2004.
Wang K, Jenwitheesuk E, Samudrala R, Mittler J. Antiviral Therapy 9: 343-352, 2004.
Wang K, Samudrala R, Mittler J. Journal of Clinical Microbiology 42: 2353-2354, 2004.
Kai Wang, John Mittler
Prediction of inhibitor resistance/susceptibility
http://protinfo.compbio.washington.edu/pirspred/
Jenwitheesuk E, Wang K, Mittler J, Samudrala R. AIDS 18: 1858-1859, 2004.
Jenwitheesuk E, Wang K, Mittler J, Samudrala R. Trends in Microbiology 13: 150-151, 2005.
Ekachai Jenwitheesuk/
Kai Wang/John Mittler
Prediction of fitness in absence of drug
Mittler J, Samudrala R. submitted, 2005.
John Mittler
Prediction of escape mutants (HIV evolution)
Is amino acid change more than one
nucleotide mutation away from query
sequence?
Yes
Exclude
No
Is this amino acid ever observed as a natural
polymorphism in untreated patients?
Yes
Include
Yes
Include
Yes
Exclude
Yes
Include
No
Is this amino acid in a database of mutants
found to have nonzero fitness in in vitro
studies such as those of Loeb et al.?
No
Is the new protein predicted to be
nonfunctional based on all-atom score
No
Does amino acid change have a high
Blosum62 or PAM score?
No
Exclude
John Mittler
Acknowledgements
Aaron Chang
David Nickle
Ekachai Jenwitheesuk
Gong Cheng
Jason McDermott
Jeremy Horst
Kai Wang
Ling-Hong Hung
Mike Inouye
Michal Guerquin
Stewart Moughon
Shing-Chung Ngan
Tianyun Liu
Zach Frazier
John Mittler and Jim Mullins
National Institutes of Health
National Science Foundation
Searle Scholars Program (Kinship Foundation)
UW Advanced Technology Initiative in Infectious Diseases
http://protinfo.compbio.washington.edu
http://bioverse.compbio.washington.edu