Molecular Basis for Bcl-2 Homology 3 Domain Recognition in the Bcl-2 Protein Family IDENTIFICATION OF CONSERVED HOT SPOT INTERACTIONS

The proteins of the Bcl-2 family are important regulators of apoptosis, or programmed cell death. These proteins regulate this fundamental biological process via the formation of heterodimers involving both pro- and anti-apoptotic family members. Disruption of the balance between anti- and pro- apoptotic Bcl-2 proteins is the cause of numerous pathologies. Bcl-xl, an anti- apoptotic protein of this family, is known to form heterodimers with multiple pro- apoptotic proteins, such as Bad, Bim, Bak, and Bid. To elucidate the molecular basis of this recognition process, we used molecular dynamics simulations coupled with the Molecular Mechanics/Poisson-Boltzmann Surface Area approach to identify the amino acids that make significant energetic contributions to the binding free energy of four complexes formed between Bcl-xl and pro- apoptotic Bcl-2 homology 3 peptides. A fifth protein-peptide complex composed of another anti- apoptotic protein, Bcl-w, in complex with the peptide from Bim was also studied. The results identified amino acids of both the anti- apoptotic proteins as well as the Bcl-2 homology 3 (BH3) domains of the pro- apoptotic proteins that make strong, recurrent interactions in the protein complexes. The calculations show that the two anti- apoptotic proteins, Bcl-xl and Bcl-w, share a similar recognition mechanism. Our results provide insight into the molecular basis for the promiscuous nature of this molecular recognition process by members of the Bcl-2 protein family. These amino acids could be targeted in the design of new mimetics that serve as scaffolds for dew antitumoral molecules.