This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ErbB family receptor-mediated signaling activates a multi-layered network mediating crucial pathways leading to cell proliferation, differentiation, and migration. Our proposed objective is to apply modeling tools at two scales: (1) biomolecular dynamics on atomistic and explicitly solvated systems, umbrella sampling, and free energy perturbation, for studying at atomic resolution, the regulatory processes in the ErbB kinases. (2) Elastic membrane simulations of membrane deformations to relate to ErbB receptor internalization and trafficking. Project 1: Employ Free Energy Perturbation (FEP) simulations to study the free energy changes due to mutations of key residues and due to ligand binding in active and inactive conformations of ErbB1 kinase. Project 2: Delineate the free energy landscape and structurally characterize the molecular pathway that describes the transition between the inactive and active conformations in wildtype ErbB1 and ErbB4 receptor tyrosine kinase dimer systems. Project 3: Compute the free energies of protein-mediated membrane deformations in highly curved membranes at the mesoscale using coarse-grained models and thermodynamic integration. The simulation studies will be synergistic with collaborative experiments done in Professor Mark Lemmon's lab at Penn. The experimental work will include X-ray crystallography, site-directed mutagenesis, as well as cellular signaling assays.
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