(295h) Insilico Multiscale Models for Identifying Driver Versus Passenger Mutations in Cancer Progression

We describe current advances in multiscale computational
modeling and simulation approaches in our laboratory combining models in structural
biology and those in systems biology. The overall aim is to build quantitative
models of signaling networks while retaining the crucial elements of molecular
specificity, which appear to be highly relevant to profiling and predictive
modeling of clinical mutations in many transformed cell lines. We discuss current
and emerging experimental and computational methods, particularly focusing on
hybrid and multiscale methods, which we have developed, and highlight several
applications in cell signaling with quantitative and predictive capabilities.
The scope of such models range from delineating protein-protein interactions to
describing clinical implications in the context of mutations in ErbB family
receptors (EGFR, HER2, HER3, and HER4) in non-small-cell lung cancer, and ALK
receptor in pediatric neuroblastoma.

Related References:

1.    Molecular Systems Biology of
ErbB1 Signaling: Bridging the Gap through Multiscale Modeling and
High-Performance Computing, Andrew Shih, Jeremy Purvis, R.
Radhakrishnan, Molecular Biosystems (A Royal Society of Chemistry
Journal), 4: 1151-1159, 2008.  Pubmed ID: 19396377

2.    Molecular Dynamics Analysis
of Conserved Hydrophobic and Hydrophilic Bond Interaction Networks in ErbB
Family Kinases, A. Shih, S. E. Telesco, S. H. Choi, M. A. Lemmon, R.
Radhakrishnan, Biochemical Journal, 2011, 436(2), 241-251. Pubmed ID: 21426301.

3.    Analysis of Somatic Mutations
in Cancer: Molecular Mechanisms of Activation in the ErbB family of Receptor
Tyrosine Kinases, A. J. Shih, S. E. Telesco, R. Radhakrishnan, Cancers, 2011,
3(1), 1195-1231; doi:10.3390/cancers3011195. Pubmed ID: 21701703.

4.    A Multiscale Modeling
Approach to Investigate Molecular Mechanisms of Pseudokinase Activation and
Drug Resistance in the HER3/ErbB3 Receptor Tyrosine Kinase Signaling Network,
S. E. Telesco, A. J. Shih, F. Jia, R. Radhakrishnan, Molecular Biosystems
(RSC Journal), 2011, 7 (6), 2066 - 2080. DOI: 10.1039/c0mb00345j. Pubmed
ID: 21509365.