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Bioenergetics
Cellular respiration and photosynthesis constitute the most fundamental energy production mechanisms for sustaining biological processes in all living cells. Bioenergetic organelles consist of sets of protein complexes and enzymes that transform a precursor, such as light, into chemical energy in the form of adenosine triphosphate (ATP) molecules. The synthesis of ATP molecules is driven by a proton gradient across the bioenergetic membrane, which is generated by one of the most ubiquitous and remarkable of all proteins, the cytochrome bc1 complex.
By using powerful tools such as molecular dynamics simulations and ab-initio quantum chemical calculations, we investigate the quinol binding and subsequent charge transfer reactions at the atomistic level.
We elucidated key aspects of the reaction mechanism such as binding motifs of the cofactor, quinol, to the protein complex, and characterized the subsequent charge transfer reaction, namely, a proton-coupled electron transfer (PCET).
Unveiling the reaction mechanism of the bc1 complex has important implications for understanding energy conversion in photosynthesis and respiration. The bc1 complex malfunctions in the respiratory chain are central to a large number of diseases associated with aging, arthritis, cancer, heart disease, diabetes, and obesity. Likewise, the high efficiency of energy conversion in the bc1 complex during photosynthesis makes it of outstanding relevance for optimal energy conversion research.
Kinase inhibition
Bruton's tyrosine kinase (BTK) plays an important role in B-Cell survival and proliferation. This kinase is often targeted, in the treatment of certain B-Cell malignancies such as some leukemias and lymphomas, with a drug inhibitor called ibrutinib. This drug binds covalently to a cysteine in the active site and renders it inactive.
By combining hybrid quantum mechanics/molecular mechanics simulations and enhanced-sampling methods, such as the string method with swarms of trajectories, we can unveil details of the reaction mechanism of BTK inhibition by ibrutinib, specifically, the Thiol-Michael addition taking place during the covalent binding.
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