Large conformational changes in proteins: signaling and other functions

Abstract

Guanine and adenine nucleotide triphosphatases, such as Ras proteins and protein kinases, undergo large conformational changes upon ligand binding in the course of their functions. New computer simulation methods have combined with experimental studies to deepen our understanding of these phenomena. In particular, a 'conformational selection' picture is emerging, where alterations in the relative populations of pre-existing conformations can best describe the conformational switching activity of these important proteins.

Figure 1

Conformational selection and induced-fit models. Conformational selection (green arrows) dictates that the unbound protein (left of figure) explores a range of conformations some of which are structurally similar to bound conformations. Interaction with binding partners (blue) leads to the preferential selection of favorable pre-existing conformations causing a corresponding shift in the population of microstates in the direction of bound conformations (right of figure). With the induced-fit model (red arrows) the bound like conformations form only after interaction with a binding partner due to specific induced structural changes rather than selection from the already present unbound ensemble.

Figure 2

Major conformational clusters in a single aMD simulation of GTP bound H-ras include GDP, GTP and intermediate like conformations. See [37] for further details.

Figure 3

Key features of the proposed DFG flipping mechanism in Abl kinases include rearrangements of helix αC and the salt bridge partner of Glu-286. Schematics are based on the kinase domain of active (A) and autoinhibited crystal structures (C), along with a cMD simulated intermediate (B). See [45] for further details © 2008 by The National Academy of Sciences of the USA