A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics

Bak is a pro-apoptotic protein and a member of the Bcl-2familythat plays a key role in apoptosis, a programmed cell death mechanismof multicellular organisms. Its activation under death stimuli triggersthe permeabilization of the mitochondrial outer membrane that representsa point of no return in the apoptotic pathway. This process is deregulatedin many tumors where Bak is inactivated, whereas in other cases likein neurodegeneration, it exhibits an excessive response leading todisorders such as the Alzheimer disease. Members of the Bcl-2 familyshare a common 3D structure, exhibiting an extremely similar orthostericbinding site, a place where both pro and antiapoptotic proteins bind.This similarity raises a selectivity issue that hampers the identificationof new drugs, capable of altering Bak activation in a selective manner.An alternative activation site triggered by antibodies has been recentlyidentified, opening the opportunity to undertake new drug discoverystudies. Despite this recent identification, an exhaustive study toidentify cryptic pockets as prospective allosteric sites has not beenyet performed. Thus, the present study aims to characterize novelhotspots in the Bak structure. For this purpose, we have carried outextensive molecular dynamics simulations using three different Baksystems including Bak in its apo form, Bak in complexwith its endogen activator Bim and an intermediate form, set up byremoving Bim from the previous complex. The results reported in thepresent work shed some light on future docking studies on Bak throughthe identification of new prospective allosteric sites, not previouslydescribed in this protein.