Biomolecular Simulations as an Integral Research and Educational Tool for Molecular Systems Biology: Application to ErbB

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

0853539 Radhakrishnan Intellectual Merit - In this post-genomic era, systems biology has provided a rational and quantitative approach to unify complex cellular interactions and comprehend modular outcomes that determine different cell fates. However, subtle differences in the molecular context of the intracellular environment (e.g., differences in phosphorylation states, between homologous proteins, isoforms, or mutants) nevertheless translate into crucial differences in the manifestations of the emergent signaling response, thereby representing a huge challenge in formulating quantitative systems-level models that truly capture such variations across distinctive cell-lines. In the context of ErbB family receptor-mediated signaling, the molecular context shapes the finer controls exercised by the cell and a quantitative description of this level of control has been a challenge. This project on molecular systems biology is based on utilizing standard and established biomolecular simulations (molecular dynamics and free energy computations) of the ErbB family receptors by leveraging the anchors (crystal structures) provided by recent progress in structural biology and introducing molecular resolution to the systems biology of ErbB-mediated signaling. The expected outcome of this project is to quantitatively and predictively describe how differences in the molecular architecture of ErbB family receptor-mediated interactions influence early signaling events and verify key predictions through collaborative cell-biology experiments performed in the laboratory. The results from this work will directly complement prior efforts in modeling differential signaling in the ErbB pathway, and together, one can expect to gain an integrated multiscale understanding of the Molecular Systems Biology of ErbB signaling. Broader Impact - This project is expected to benefit many novel applications of multiscale systems biology and nanobiotechnology. In particular, the study of ErbB signaling at the level of receptor activation will provide a direct route to discern signaling triggered by molecular perturbations which can impact our understanding of the link between cellular proliferative signals and higher order functions such as tissue-growth homeostasis, cardiac and neuronal development. Complementing the interdisciplinary research program, the educational and outreach programs are constituted by rigorous and visionary research training for undergraduate students in engineering and biology. To achieve broader impact in complementing the undergraduate research experience, a three dimensional stereo environment for visualizing biomolecular structure and animations is established and utilized for the instruction of molecular modeling and simulation techniques at the undergraduate and graduate levels.