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CFTR functions as an anion channel, the gating of which is controlled by long-range allosteric communications. Allostery also has direct bearings on CF treatment: the most effective CFTR drugs modulate its activity allosterically. Herein, we integrated Gaussian network model, transfer entropy, and anisotropic normal mode-Langevin dynamics and investigated the allosteric communications network of CFTR. The results are in remarkable agreement with experimental observations and mutational analysis and provide extensive novel insight. We identified residues that serve as pivotal allosteric sources and transducers, many of which correspond to disease-causing mutations. We find that in the ATP-free form, dynamic fluctuations of the residues that comprise the ATP-binding sites facilitate the initial binding of the nucleotide. Subsequent binding of ATP then brings to the fore and focuses on dynamic fluctuations that were present in a latent and diffuse form in the absence of ATP. We demonstrate that drugs that potentiate CFTR\u2019s conductance do so not by directly acting on the gating residues, but rather by mimicking the allosteric signal sent by the ATP-binding sites. We have also uncovered a previously undiscovered allosteric \u2018hotspot\u2019 located proximal to the docking site of the phosphorylated regulatory (R) domain, thereby establishing a molecular foundation for its phosphorylation-dependent excitatory role. This study unveils the molecular underpinnings of allosteric connectivity within CFTR and highlights a novel allosteric \u2018hotspot\u2019 that could serve as a promising target for the development of novel therapeutic interventions.<\/jats:p>","DOI":"10.7554\/elife.88659","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T10:42:11Z","timestamp":1687776131000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88659","source":"Crossref","is-referenced-by-count":2,"title":["Computational analysis of long-range allosteric communications in CFTR"],"prefix":"10.7554","volume":"12","author":[{"given":"Ayca","family":"Ersoy","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03z9tma90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemical Engineering, Bogazici University","place":["Istanbul, Turkey"]},{"id":[{"id":"https:\/\/ror.org\/03z9tma90","id-type":"ROR","asserted-by":"publisher"}],"name":"Polymer Research 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