Conformational transition of the catalytic domain of Src studied by computational approaches.

摘要

The activity regulation of the Src family kinases (SFKs) involves a conformational transition of the catalytic domain between a canonical active structure and a less-common inactive structure. Computations with a coarse-grained Gō model that features two energy basins were used to study the conformational transition process. Free energy landscapes, calculated based on replica exchange molecular dynamics sampling, provided information about important structural coordinates. Based on the landscapes, the relative motion of the N- and C-terminal lobes and the conformational change of the C-terminal part of the activation loop (A-loop) are facile motions that do not correspond to the crossing of the major free energy barrier, whereas the displacement of the αC helix closely correlates with an energetic reaction coordinate. To investigate the sequence of events during the transition process, the maximum flux transition path (MFTP) method was used to locate optimal transition pathways between the active and inactive states. In a low-dimensional collective variable space, three different initial paths converged to a same final path. Going from the active to the inactive state in this optimized path, the A-loop folds into the catalytic cleft and presents its N-terminal segment in an inactive-like conformation before the αC helix moves outward. Examining the evolution of the path during the optimization revealed that such a sequence reduces the height of a major free energy barrier induced by the displacement of the αC helix. Similar results obtained for a remotely related kinase CDK2 confirmed that the highlighted role of the αC helix is a robust feature determined by the topology of the structures.