Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations
Fig 1
Building “exemplars” from surface pockets.
(A) Bcl-xL (grey surface) is shown in complex with an inhibitor (spheres). (B) The protein surface features a large pocket (small white spheres) that is complementary in shape to the inhibitor. (C) From this surface pocket, an “exemplar” is built: a map of the “perfect” ligand to complement this protein surface, without considerations of atom connectivity. The exemplar is comprised of hydrogen bond donors (yellow) and acceptors (magenta) that complement surface polar groups on the protein, and hydrophobic atoms that fill the remainder of the surface pocket (cyan). In the studies we report here, we will use the shape and chemical features of the exemplar as a proxy for the shape and chemical features of the protein surface pocket.