J Chem Inf Model - Molecular determinants of Bim(BH3) peptide binding to pro-survival proteins.

Tópicos

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Resumo

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.

Resumo Limpo

protein bcl famili regul apoptosi format heterodim antiapoptot prosurviv protein proapoptot prodeath protein overexpress antiapoptot protein contribut progress mani cancer also confer resist chemo radiotherapeut treatment demonstr peptid contain bh domain proapoptot bcl famili member abl bind inhibit antiapoptot protein reason design small molecul mimick bh domain proapoptot protein emerg promis therapeut strategi cancer treatment last year howev bh domain exhibit differ affin bind antiapoptot protein wherea bimbh pumabh abl bind antiapoptot protein other like badbh bmfbh show prefer protein other consequ abil bhmimet kill tumor cell will depend bh peptid use templat thus will select paninhibit effect recent suggest last approach interest therefor present work aim elucid nonselect peptid bimbh abl bind bcl famili antiapoptot protein unravel molecular determin paninhibit use mmpbgbsa approach calcul bind free energi differ complex studi determin residu peptid largest contribut complex format result obtain present work show bind bimbh prosurviv protein main hydrophob specif interact fulli distribut along peptid sequenc

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