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. 2020 Aug 19;3:452. doi: 10.1038/s42003-020-01173-z

Fig. 4. MD simulations of bedaquiline bound to the yeast ATP synthase.

Fig. 4

a Simulation system, comprising the c-ring (yellow surface/cartoon) embedded in a bilayer of 233POPC lipids and a 100 mM NaCl buffer plus counter-ions (magenta/green). Three bedaquiline molecules (spheres) are initially bound to the c-ring (see “Methods”). The total number of atoms is ~95,000, enclosed in a periodic box of 100 × 100 × 92 Å. Water molecules (ca. 18,000) and lipid hydrogen atoms are omitted from clarity. b Time series of the distance between the carboxyl group of cGlu69 and the amine group of BDQ, for each of the three BDQ molecules initially bound to the c-ring. Data are shown for two cases: neutral BDQ (and protonated cGlu59), and protonated BDQ (and ionized cGlu59). For clarity, data are shown only for one 100-ns trajectory; two additional 100-ns trajectories were calculated independently, with the same result. c Close-up of the most populated binding modes of protonated BDQ during the simulations (pose A: 44%; pose B: 43%). Neighboring side chains in the protein are highlighted. Nonpolar hydrogen atoms are omitted for clarity. d Simulation system, including the c-ring (yellow surface/cartoon), subunit-a (red surface/cartoon) and subunits-b and -8 (blue surface/cartoon) embedded in a bilayer of 254POPC lipids and a 100 mM NaCl buffer, plus counter-ions (magenta/green). One bedaquiline molecule (spheres) is initially bound to the c-ring, at the a–c interface. The total number of atoms is ~109,000, enclosed in a periodic box of 90 × 125 × 101 Å. Water molecules (ca. 20,000) and lipid hydrogen atoms are omitted from clarity. e Time series of the distance between the carboxyl group of cGlu69 and the amine group of BDQ, for two cases: neutral BDQ (and protonated cGlu59), and protonated BDQ (and ionized cGlu59). f Close-up of the proposed binding mode for protonated BDQ. Neighboring side chains in the both the c-ring (yellow) and subunit-a (red) are highlighted. Nonpolar hydrogen atoms are omitted for clarity. g Overlay of the binding pose proposed on the basis of simulation data and the experimental cryo-EM density map, contoured at 6σ.