Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery

Abstract

Decoding molecular flexibility in order to understand and predict biological processes—applying the principles of dynamic-structure-activity relationships (DSAR)—becomes a necessity when attempting to design selective and specific inhibitors of a protein that has overlapping interaction surfaces with its upstream and downstream partners along its signaling cascade. Ras proteins are molecular switches that meet this definition perfectly. The close-lying P-loop and the highly flexible switch I and switch II regions are the site of nucleotide-, assisting-, and effector-protein binding. Oncogenic mutations that also appear in this region do not cause easily characterized overall structural changes, due partly to the inherent conformational heterogeneity and pliability of these segments. In this review, we present an overview of the results obtained using approaches targeting Ras dynamics, such as nuclear magnetic resonance (NMR) measurements and experiment-based modeling calculations (mostly molecular dynamics (MD) simulations). These methodologies were successfully used to decipher the mutant- and isoform-specific nature of certain transient states, far-lying allosteric sites, and the internal interaction networks, as well as the interconnectivity of the catalytic and membrane-binding regions. This opens new therapeutic potential: the discovered interaction hotspots present hitherto not targeted, selective sites for drug design efforts in diverse locations of the protein matrix.