This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Integrins are major cell-adhesion receptors and bidirectional signal transducers across the cell membrane. Signals are transmitted between the extracellular ligand-binding site and the cytoplasmic tails through large-scale allosteric conformation changes with more than 100 AA spatial extension. Here we study the one-directional signal transduction--outside-in signaling by molecular dynamics simulations. This signaling process is triggered by binding of extracellular ligands by integrins, followed by structural transitions from the bent conformation (about 100 AA spatial extension) to the extended conformation (more than 200 AA spatial extension). Molecular dynamics simulations will be performed for the complex of $alpha_{mathrm{IIb}}beta_3$ integrin in the bent conformation bound with a poly-peptide ligand (12 residues) from the C-terminus of Fibrinogen $gamma$ chain in an aqueous solution. To mimic physiological conditions in cell adhesions, the cytoplasmic tails of $alpha$ and $beta$ subunits of the integrin are confined to a planar surface mimicking the cell membrane; the ligand is being pulled perpendicular to the ``cell surface'' by the extracellular matrix. The external pulling force will trigger the structural transition of the integrin and we want to capture both the final structure and the transition path by molecular dynamics simulations. Due to the large size of the protein (more than 24 000 atoms and 11 domains) and the large spatial extension (more than 100 AA), the total number of atoms including solvent is estimated to be more than 250 000. The benchmark is estimated to be 15 s per time step on a single processor; one nano second simulation will take more than $10^7mathrm{s}approx$ 3000 CPU hours, which is unrealistic with small clusters with fewer than 30 nodes. We therefore request computing resources from PSC to perform the calculations. The simulations will be carried out using the NAMD package developed by Dr.~Klaus Schulten's group from University of Illinois, Urbana Champaign. The simulation results will offer insights into the structural basis of signal transduction by allosteric conformation changes and test different hypothesis on the mechanism of integrin affinity regulation. The final conformation also provides the first model for an extended integrin molecule under physiological conditions.
Showing the most recent 10 out of 292 publications
