title: Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories.
abstract: The Src-family kinases are allosteric enzymes that play a key role in the regulation of cell growth and proliferation. In response to cellular signals, they undergo large conformational changes to switch between distinct inactive and active states. A computational strategy for characterizing the conformational transition pathway is presented to bridge the inactive and active states of the catalytic domain of Hck. The information from a large number (78) of independent all-atom molecular dynamics trajectories with explicit solvent is combined together to assemble a connectivity map of the conformational transition. Two intermediate states along the activation pathways are identified, and their structural features are characterized. A coarse free-energy landscape is built in terms of the collective motions corresponding to the opening of the activation loop (A-loop) and the rotation of the alphaC helix. This landscape shows that the protein can adopt a multitude of conformations in which the A-loop is partially open, while the alphaC helix remains in the orientation characteristic of the inactive conformation. The complete transition leading to the active conformation requires a concerted movement involving further opening of the A-loop, the relative alignment of N-lobe and C-lobe, and the rotation of the alphaC helix needed to recruit the residues necessary for catalysis in the active site. The analysis leads to a dynamic view of the full-length kinase activation, whereby transitions of the catalytic domain to intermediate configurations with a partially open A-loop are permitted, even while the SH2-SH3 clamp remains fully engaged. These transitions would render Y416 available for the transphosphorylation event that ultimately locks down the active state. The results provide a broad framework for picturing the conformational transitions leading to kinase activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Sichun
authors.initials: S
authors.lastname: Yang
authors.forename: Nilesh K
authors.initials: NK
authors.lastname: Banavali
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
mesh_terms: D004789:Enzyme Activation; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D019061:src-Family Kinases / Q000737:chemistry*
chemical_list: D007477:Ions; D019061:src-Family Kinases