Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides

Abstract

Apoptosis is a key procedure for all cells. Understanding this process and its regulation has been a subject of study in the last decades. Bcl-2 family of proteins are involved in the regulation of the apoptosis through the formation of homodimers or heterodimers between anti-apoptotic and pro-apoptotic proteins. Deregulation of pro-apoptotic proteins contributes to the progression of many tumour processes. Understanding how these proteins are activated is key to find new anti-cancer treatments. As no drug capable of activating Bak has been discovered yet, studying the structural and energetic insights of the binding of the known Bak activators, BH3 peptides, is essential to design new small molecules that resemble their binding to Bak. Recently, a BH3 Bim analogue has been discovered which inactivates Bak instead of activating it. Therefore, the present work is aimed to identify how BH3 peptides activate or inactivate Bak and determine any difference between them. Determination of the structural differences between the complexes with the activator and the inhibitor has been carried out by means of the study of the fluctuations of the corresponding Principal Components. Moreover, to calculate the binding free energy of the different complexes and to determine which residues of the peptide have the largest contribution to complex formation, MMPB/GBSA approaches are used. Results obtained in this work show differences in complexes with the activator and the inhibitor in structural and energetic terms, which can be used in the design of new molecules that could activate or inactivate pro-apoptotic Bak.