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The enzyme consists of two distinct rotors: a membrane\u2010embedded F\u2092\u00a0unit and a cytosolic catalytic F\n                    <jats:sub>1<\/jats:sub>\n                    unit, along with a stator, a central stalk, and a heterodimeric peripheral stalk (PS). As the F\n                    <jats:sub>0<\/jats:sub>\n                    region hosts critical drug\u2010binding pockets, it has gained significant interest. This study focuses on local structural dynamics at the leading site in the presence of bedaquiline (BDQ). All\u2010atom molecular dynamics simulations were performed using GROMACS in a heterogeneous bilayer composed of phosphoinositol, phosphoethanolamine, phosphoglycerol, and cardiolipin (PI: PE: PG: CL) in a 32:42:4:50 ratio. The results revealed key interactions of BDQ with cL\n                    <jats:sup>59<\/jats:sup>\n                    , cF\n                    <jats:sup>65<\/jats:sup>\n                    , cE\n                    <jats:sup>61<\/jats:sup>\n                    , cA\n                    <jats:sup>62<\/jats:sup>\n                    , cI\n                    <jats:sup>55<\/jats:sup>\n                    , cI\n                    <jats:sup>66<\/jats:sup>\n                    , cG\n                    <jats:sup>58<\/jats:sup>\n                    , aI\n                    <jats:sup>215<\/jats:sup>\n                    , and aF\n                    <jats:sup>219<\/jats:sup>\n                    at the a\/c interface, consistent with energetically favored binding conformation. Quantitative lipid contact analysis revealed higher CL interactions with BDQ at leading site together with interfacial water molecules, whereas protein\u2010lipid contacts based on only lipid headgroup (P\u2010atoms) analysis remained independent of lipid abundance in the system. RMSD and RMSF revealed BDQ\u2010induced fluctuations in the outer helix of subunit\u2010c, while subunit\u2010a remained comparatively more stable during the simulation. Distance analysis further indicated that the ligand remains confined within the binding region despite local flexibility. We further identified putative non\u2010collinear proton channels, which showed no significant global perturbation upon BDQ binding. Residues aG\n                    <jats:sup>195<\/jats:sup>\n                    , aN\n                    <jats:sup>105<\/jats:sup>\n                    , aD\n                    <jats:sup>220<\/jats:sup>\n                    , aN\n                    <jats:sup>190<\/jats:sup>\n                    , aQ\n                    <jats:sup>227<\/jats:sup>\n                    , cE\n                    <jats:sup>61<\/jats:sup>\n                    (inlet side), cE\n                    <jats:sup>61<\/jats:sup>\n                    (outlet side), aE\n                    <jats:sup>176<\/jats:sup>\n                    , aE\n                    <jats:sup>175<\/jats:sup>\n                    , aA\n                    <jats:sup>178<\/jats:sup>\n                    , aK\n                    <jats:sup>179<\/jats:sup>\n                    , aS\n                    <jats:sup>182<\/jats:sup>\n                    , aY\n                    <jats:sup>238<\/jats:sup>\n                    , aQ\n                    <jats:sup>110<\/jats:sup>\n                    , aF\n                    <jats:sup>192<\/jats:sup>\n                    , aL\n                    <jats:sup>122<\/jats:sup>\n                    form the two half channels in\n                    <jats:italic>Mtb<\/jats:italic>\n                    . The pooled water\u2010count analysis for channels showed similar hydration levels in all simulated systems. We hypothesize that selective targeting of the leading pocket by newer drugs, in the presence of CL lipids, can modulate the proton inlet channel. The heterogeneous bilayer supports the structural and functional integrity of the membrane and ATPase complex. A CL\u2010enriched membrane environment may provide a useful framework for investigating membrane\u2010associated effects of BDQ and its analogs. Chain\u2010wise analysis showed synchronous movement of the PS subunits and twisting of the \u03b4\u2010binding region, which may be perturbed in the presence of the F\n                    <jats:sub>1<\/jats:sub>\n                    unit. The dynamics also revealed subunit\u2010b\u03b4 involvement with the subunit\u2010a at the leading pocket, a less studied PS and stator function. Identifying residue\u2010specific interactions between PS could help to reveal its mechanical function. Together, these results provide complementary dynamic insights into BDQ at the leading pocket in a physiologically mimicked membrane environment and potentially support its relevance as a target site for the development of anti\u2010TB compounds targeting ATPase.\n                  <\/jats:p>","DOI":"10.1002\/jcb.70095","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T13:56:04Z","timestamp":1780149364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bedaquiline Binding at the Leading Site of\n                    <i>Mycobacterium tuberculosis<\/i>\n                    ATP Synthase Induces Distinct Structural and Dynamic Changes"],"prefix":"10.1002","volume":"127","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0841-5414","authenticated-orcid":false,"given":"Pragya","family":"Anand","sequence":"first","affiliation":[{"name":"Department of Biotechnology, School of Life 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