Proteins of the Bcl-2 family regulate apoptosis through the formation of heterodimers between antiapoptotic or pro-survival
proteins and proapoptotic or pro-death
proteins. Overexpression of antiapoptotic
proteins not only contributes to the progression of many
cancers, but also confers resistance to the chemo- and radiotherapeutic treatments. It has been demonstrated that
peptides containing the BH3 domain of proapoptotic Bcl-2 family members are able to bind and inhibit antiapoptotic
proteins. For this reason, the design of small molecules mimicking the BH3 domain of proapoptotic
proteins has emerged as a promising therapeutic strategy for
cancer treatment during the last years. However, BH3 domains exhibit different affinities for binding to antiapoptotic
proteins; whereas Bim(BH3) and Puma(BH3) are able to bind all antiapoptotic
proteins, others like Bad(BH3) and Bmf(BH3) show preference for some
proteins over others. Consequently, the ability of a BH3-mimetic to kill
tumor cells will depend on the
BH3 peptide used as template and thus will have a selective or pan-inhibition effect. Recently, it has been suggested that this last approach could be interesting. Therefore, the present work is aimed to elucidate how the nonselective
peptide Bim(BH3) is able to bind to all of the Bcl-2 family antiapoptotic
proteins. To unravel the molecular determinants of this pan-inhibition, we used the MM-PB/GBSA approaches to calculate the binding free energy of the different complexes studied and to determine which residues of the
peptide have the largest contribution to complex formation. Results obtained in the present work show that the binding of Bim(BH3) to pro-survival
proteins is mainly hydrophobic and that specific interactions are fully distributed along the
peptide sequence.