Briggs, James M.2019-11-07August 2012019-08August 201https://hdl.handle.net/10657/5315The F1FO – ATP synthase has been the object of study in the scientific community both from theory and experiment over the past couple of decades. The ATP synthase is a protein complex in the mitochondrial membrane that efficiently converts the cell’s transmembrane proton gradient into chemical energy stored as adenosine triphosphate (ATP). The protein is made of two molecular motors, F1 and FO, coupled by the central stalk. The free energy used for the synthesis of ATP is in the form of protons moving down the electrochemical gradient from the inner-membrane space to the mitochondrial matrix via the two offset half-channels. The membrane bound part of ATP synthase, FO, converts the transmembrane electrochemical potential into mechanical rotation of the rotor in FO and the stalk physically connected to it. Mutations in a gene encoding ATP synthase are proven to affect its function and cause severe syndromes related to energy deficiency. In this dissertation, we study, using molecular dynamics (MD) simulations, the formation of the half-channels within the stator part of FO. These half-channels enable the proton translocation to and from the rotor portion, known as the c-ring. Combining MD with the protein structure network paths and hydrogen-bonding network analysis, we were able to observe clear evidence for proton pathways and compare our results with previous experimental results. We also report studies of leucine-arginine and leucine-proline amino acid replacements, encoded by the T-G and T-C point mutations at locus 8993 of mtDNA. Our results suggest, for the first time, that these mutations adversely affect water half-channels, and consequently impair the ability of the ATP synthase to produce ATP.application/pdfengThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).F1Fo ATP synthaseProton transportFo half-channelsMtATP6 mutations2019-11-07Thesisborn digital