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Speaker: Angela Barragan (U. Chicago)
Topic: Unveiling the reaction mechanisms of macromolecules using a computational microscope
Abstract: The reaction mechanisms involving enzymes and other protein complexes are governed by their quantum-mechanical nature. For this reason, it is extremely challenging to establish key features of their reaction mechanisms, even more so when these combine quantum effects at the electron level together with conformational changes at the biomolecular level.To unveil such biological processes, we use computational methods that efficiently describe classically the interatomic interactions, while taking into account quantum mechanical effects of the region where reactions take place. In this talk, I will highlight two enzymes of biological significance, and discuss how the combination of different computational approaches allowed us to uncover, with unprecedented detail, their reaction mechanisms. In particular, I will discuss the bc1 complex, an enzyme that plays a fundamental role in cellular energy production, and which features a proton-coupled electron transfer reaction with a high kinetic isotope effect. I will also present my ongoing investigations on the inhibition of Bruton’s tyrosine kinase, which is essential in the proliferation of B cells and is often targeted in the treatment of certain types of blood cancers. The strategy to elucidate the reaction mechanism, in this case, is aided by enhanced sampling methods in tandem with hybrid quantum mechanics/molecular mechanics simulations.