Target the More Druggable Protein States in a Highly Dynamic Protein--Protein Interaction System.

The proteins of the Bcl-2 family play key roles in the regulation of programmed cell death by controlling the integrity of the outer mitochondrial membrane and the initiation of the apoptosis process. We performed extensive molecular dynamics simulations to investigate the conformational flexibility of the Bcl-xL protein in both the apo and holo (with Bad peptide and ABT-737) states. The accelerated molecular dynamics method implemented in Amber 14 was used to produce broader conformational sampling of 200 ns simulations. The pocket mining method based on the variational implicit-solvent model tracks the dynamic evolution of the ligand binding site with a druggability score characterizing the maximal affinity achievable by a drug-like molecule. Major movements were observed around the α3-helical domain and the loop region connecting the α1 and α2 helices, reshaping the ligand interaction in the BH3 binding groove. Starting with the apo crystal structure, which is recognized as “closed” and undruggable, th...