Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations
Fig 5
Comparison of “pocket space” sampled by each Bcl-2 family member.
(A) A projection built using ensembles collected from simulations of several Bcl-2 family members: Bcl-xL (magenta), Bcl-2 (green), Mcl-1 (red), Bcl-w (orange), and Bax (cyan). Bid and Ced-9 were used in generating the projection, but for clarity are not included on this map. Target residues derived from the Bcl-xL protein interaction site were used in generating exemplars shown on the Bcl-xL and Bcl-2 MDS plots, whereas target residues derived from the Mcl-1 protein interaction site were used in generating exemplars shown on the Mcl-1 MDS plots. For each of Bcl-xL, Bcl-2, and Mcl-1 we observe a distinct region of conformational space (“D”) that is not sampled by any other Bcl-2 family member. (B) Comparison of an exemplar from each “distinct” region to the corresponding unbound (“U”) or peptide-bound (“P”) protein structure from which the simulation was initiated. (C) Comparison of the conformation harboring the “distinct” pocket to the corresponding unbound/peptide-bound protein structure from which the simulation was initiated.