PRISM Seminar Series- Ravi Radhakrishnan
05/14/08
Ravi Radhakrishnan
Molecular Systems Biology through Multiscale Modeling and High-Performance Computing
University of Pennsylvania
Bioengineering
Abstract:
Ravi Radhakrishnan, University of Pennsylvania Assistant Professor of Bioengineering, School of Engineering and Applied Sciences Assistant Professor of Biochemistry and Biophysics, School of Medicine
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 mutant proteins) nevertheless translate into crucial differences in the manifestations of the emergent signaling responses, thereby representing a huge challenge in formulating quantitative systems-level models that truly capture such variations across distinctive cell-lines.
This talk is focuses on the intersection of structural biology and intracellular signaling. Specifically, we employ a battery of simulation approaches [1] including molecular dynamics, mixed quantum mechanics molecular mechanics, and free energy sampling to study regulatory processes of biomolecular systems, along with deterministic, stochastic, and hybrid multiscale methods [2] to study dynamical processes in cell membranes and in signal transduction. The overarching motive is the successful incorporation of the molecular context into quantitative cell signaling models. The foundations and applications of this approach, its predictive ability [3], and its value as a complimentary tool to biochemical, cellular, and single-molecule experiments, will be discussed via two specific intracellular cell signaling pathways, namely, DNA repair and growth factor-mediated proliferation and survival [1].
[1] Y. Liu§, J. Purvis§, A. Shih, J. Weinstein, N. Agrawal, R.
Radhakrishnan, ?A multiscale computational approach to dissect early events in the Erb family receptor mediated activation, preferential signaling, and relevance to oncogenic transformations?, 2007, Annals of Biomedical Engineering; 35, 1012-1025 § these authors contributed equally. Pubmed ID: 17273938.
[2] J. Weinstein, R. Radhakrishnan, KMC-TDGL, a coarse-grained methodology for simulating interfacial dynamics in complex fluids:
application to protein-mediated membrane processes, 2006, Mol. Phys., 104, 3653?3666, 2006.
[3] R. Venkatramani and R. Radhakrishnan, A computational study of the force dependence of phosphoryl transfer during DNA synthesis by a high fidelity polymerase, 2008, Physical Review Letters, in press.
About Ravi Radhakrishnan's Research:
"With the objective of designing drugs rationally and customized to specfic patients, we investigate biochemical phenomena at various length and timescales from electronic structure to signaling pathways by employing tools from computational biology, statistical mechanics, quantum mechanics, and high performance computing. My research interests lie in the interface of chemical physics and molecular biology and is currently focussed on biophysical and biochemical aspects of carcinogenesis, therapeutic inhibition of signaling enzymes, RNA catalysis, membrane phenomena, and resistance mechanisms in antibiotics."