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By analyzing KRas and HRas X-ray structures, we developed a novel strategy that involves the design of a series of “synthetic” or “artificial” KRas mutations, namely T20I, D57E, D57F, T58A, T58V, and G60A, individually introduced into KRas with the G12C natural pathogenic mutation to create double mutants that we would expect to enhance compound binding to the switch II pocket. The goal of using these mutants is to induce greater overall flexibility of the KRas structure to allow the switch II pocket (S-IIP) to open more frequently in the absence of a C12-covalently bound ligand. We developed sensitive assays for the Raf:KRas(GTP) interaction and SOS-driven GDP/GTP exchange to assess these KRas proteins, including the wild-type form, a mutant frequently found in human cancers (G12C), and the “artificial” G12C double mutants. By characterizing these KRas mutants, we hoped to identify at least one mutant that may provide enough flexibility for non-covalent binding to the switch II pocket, thus facilitating future non-covalent compound screening. The results of these assays provide preliminary support that some of the studied mutants demonstrate increased protein flexibility relative to that of KRas(G12C). This strategy of slightly increasing protein flexibility or destabilization through the introduction of selected mutations may be applied to other proteins for which low assay sensitivity is due to transient, high-energy, open-form binding sites.