Central role of electrostatics in mediating the interactions of Bax with mitochondrial outer membrane at the beginning of apoptosis.

OMAR JAURE; FERNANDO ZAMARREÑO; DIEGO OBIOL ; MARÍA JULIA AMUNDARAIN; JUAN FRANCISCO VISO; MARCELO D. COSTABEL

La Plata

Congreso; XLVII Reunión Anual de la Sociedad Argntina de Biofísica; 2018

Sociedad Argentina de Biofísica

The binding of proteins to the membrane surface plays a critical role in a wide variety of biological processes. It has been observed that the membrane association of many proteins is mediated by non-specific electrostatic interactions between a group of basic residues in the protein and acid phospholipids in the membrane, thus determining its activity and regulation. This is the case of the Bax protein, a pro-apoptotic member of the Bcl-2 family of proteins that remains inactive until it receives a signal of cell death. The activation process consists of initial conformational changes, translocation to the mitochondrial outer membrane(MOM), insertion, oligomerization, pore formation and consequent release ofapoptogenic factors.Free Electrostatic Energy of Binding, was computed using Finite Difference PoissonBoltzmann Equation (FDPB) method as implemented in software APBS (AdaptivePoisson Boltzmann Solver). This type of calculations provided a starting point forfurther computational analysis through molecular dynamics simulations (MD). Tothis end, we used GROMACS simulation package.The way in which the charge is distributed over the surface of Bax may haveprofound implications for the translocation to MOM at the beginning of theapoptotic process. For this reason we carried out an exhaustive analysis of theequipotential surfaces of Bax facing membranes with an increasing content ofanionic lipids. In addition, we observed that the region responsible for theelectrostatic association between Bax and membrane is relatively flat. Thisphysical characteristic makes it possible to differentiate between two possiblestates that Bax might adopt when approaching the membrane: the peripheralunion of Bax to the membrane in an inactive state, and Bax oriented for thecorrect insertion in MOM. In the present work, we demonstrated the influence ofnon-specific electrostatic interactions in the first approach between Bax-membrane.