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It remains unclear how efflux pumps can maintain this broad spectrum specificity to diverse drug molecules while limiting the efflux of other cytoplasmic content. We have investigated the origins of this broad specificity using theoretical models informed by the experimentally determined structural and kinetic properties of efflux pumps. We developed a set of mathematical models describing operation of efflux pumps as a discrete cyclic stochastic process across a network of states characterizing pump conformations and the presence\/absence of bound ligands and protons. These include a minimal three-state model that lends itself to clear analytic calculations as well as a five-state model that relaxes some of the simpler model\u2019s most strict assumptions. We found that the pump specificity is determined not solely by the drug affinity to the pump\u2013as is commonly assumed\u2013but it is also directly affected by the periplasmic pH and the transmembrane potential. Therefore, changes to the proton concentration gradient and voltage drop across the membrane can influence how effective the pump is at extruding a particular drug molecule. Furthermore, we found that while both the proton concentration gradient across the membrane and the transmembrane potential contribute to the thermodynamic force driving the pump, their effects on the efflux enter not strictly in a combined proton motive force. Rather, they have two distinguishable effects on the overall throughput. These results highlight the unexpected effects of thermodynamic driving forces out of equilibrium and illustrate how efflux pump structure and function are conducive to the emergence of multidrug resistance.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012772","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T16:49:57Z","timestamp":1738255797000},"page":"e1012772","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Specificity and tunability of efflux pumps: A new role for the proton 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