Computational Studies of the X-Linked Inhibitor of Apoptosis Complex Formation with Caspase-9 and a Small Antagonist.

Apoptosis is self-programmed cell death. The X-linked inhibitor of apoptosis (XIAP) is known to inhibit caspase proteins, the key players in apoptosis. When this happens, the cells become cancerous as they cannot die naturally. XIAP inhibitors are often overexpressed in cancer tissue. Presented in this article are the results of simulations of XIAP-caspase and XIAP-antagonist complexes. It has been previously established experimentally that low intensity ultrasound promotes apoptosis and increases the therapeutic effect of some XIAP-caspase interaction antagonists. The resulting calculated complex formation energies produced in this work were used with a simple multiscale model as an example of applying such energetic results for estimating the effects of ultrasound on these complexes. The microscopic simulations have been carried out with molecular mechanics employing an all-atom description of the molecules with the OPLS-AA and polarizable force field (PFF) formalisms. It has been determined that the interaction energies in the XIAP-caspase-9 pair with both OPLS and PFF are roughly the same and in the 30-40 kcal/mol range, while PFF predicts a higher magnitude of energy of the XIAP-antagonist complex formation (ca. 100 kcal/mol vs ca. 40 kcal/mol), thus probably being more adequate in reproducing the inhibition abilities of this low molecular weight antagonist. The presented study of the ultrasound effect leads to the conclusion that it is most likely based on the cavitation accompanying the ultrasound irradiation of the cells and not on a simple frequency resonance, as was suggested by some authors.