Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories Export

@article{citeulike:4163342, abstract = {10.1073/pnas.0808261106 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 \^{I}±C helix. This landscape shows that the protein can adopt a multitude of conformations in which the A-loop is partially open, while the \^{I}±C 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 \^{I}±C 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.}, author = {Yang, Sichun and Banavali, Nilesh K. and Roux, Beno\~{A}®t}, citeulike-article-id = {4163342}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0808261106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/10/3776.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/10/3776.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19225111}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19225111}, day = {10}, doi = {10.1073/pnas.0808261106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, keywords = {allostery, conformational\_flexibility, energylandscape, freeenergy, function, kinase}, month = {March}, number = {10}, pages = {3776--3781}, posted-at = {2009-11-07 16:30:16}, priority = {2}, title = {Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories}, url = {http://dx.doi.org/10.1073/pnas.0808261106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:4163342 L3 - citeulike-article-id:4163342 N2 - 10.1073/pnas.0808261106 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 αC helix. This landscape shows that the protein can adopt a multitude of conformations in which the A-loop is partially open, while the αC 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 αC 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. IS - 10 JF - Proceedings of the National Academy of Sciences SN - 1091-6490 EP - 3781 TI - Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories VL - 106 SP - 3776 KW - allostery KW - conformational_flexibility KW - energylandscape KW - freeenergy KW - function KW - kinase AU - Yang, Sichun AU - Banavali, Nilesh AU - Roux, Benoît PY - 2009/03/10/ UR - http://dx.doi.org/10.1073/pnas.0808261106 ER -