  The molecular origins of proteins' functions are a combinatorial search
problem in the proteins' sequence space, which requires enormous resources to
solve. However, evolution has already solved this optimization problem for us,
leaving behind suboptimal solutions along the way. Comparing suboptimal
proteins along the evolutionary pathway, or ancestors, with more optimal modern
proteins can lead us to the exact molecular origins of a particular function.
In this paper, we study the long-standing question of the selectivity of
Imatinib, an anti-cancer kinase inhibitor drug. We study two related kinases,
Src and Abl, and four of their common ancestors, to which Imatinib has
significantly different affinities. Our results show that the orientation of
the N-lobe with respect to the C-lobe varies between the kinases along their
evolutionary pathway and is consistent with Imatinib's inhibition constants as
measured experimentally. The conformation of the DFG-motif (Asp-Phe-Gly) and
the structure of the P-loop also seem to have different stable conformations
along the evolutionary pathway, which is aligned with Imatinib's affinity.
