Folding Forum

The Src family protein tyrosine kinases are enzymes that play key roles in transducing cellular signals regulating cell growth, differentiation, proliferation, migration and survival. These enzymes are responsible for diseases such as cancer in which the cells undergo uncontrolled growth and proliferation. Crystallographic x-ray structures of human c-Src in the inactive and active conformation allow clear structural distinctions to be drawn between the inactive and active states. Those x-ray structures, though rich in information about the two end-points of the activation event, do not show how the activation occurs and how it might be regulated. Simulations and computational models, at different levels of approximation, can complement some of the missing information about Src and help address these important questions. Characterizing conformational transitions in large biomolecules such as Src is challenging, however, because the slow processes are not easily observed during simple unbiased molecular dynamics (MD) simulations. To circumvent those difficulties, previous studies of Src by our collaborators have used biased sampling techniques such as string method to get the series of structures which show the structural changes involved in the activation process. In this project, we perform simulations of src kinase from the structures obtained using the string method to get a more detailed picture of the activation process.