S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism

• Published in: Journal of molecular modeling 2024-02, Vol.30 (2), p.39-39, Article 39
• Main Authors: Ge, Yutong, Luo, Qing, Liu, Ling, Shi, Quanshan, Zhang, Zhigang, Yue, Xinru, Tang, Lingkai, Liang, Li, Hu, Jianping, Ouyang, Weiwei
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Bond energy; Cell Membrane; Cell membranes; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Drug resistance; Ethylenediamines; Hydrogen bonds; Inhibitors; Ion Channels; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Medicine; Molecular structure; Mutation; Mycobacterium tuberculosis - genetics; Original Paper; Protons; Quantum mechanics; Substrates; Theoretical and Computational Chemistry; Transfer functions; Tuberculosis
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-023-05814-y

Context Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis ( Mtb ) and has become a potent anti-tuberculosis target. SQ109 is an ethambutol (EMB) analogue, as a novel anti-tuberculosis drug, can effectively inhibit MmpL3, and has completed phase 2b-3 clinical trials. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows significant resistance to the inhibitor SQ109, while the specific action mechanism remains unclear. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport efficiency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant but also aids the development of novel anti-tuberculosis inhibitors. Methods In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics, and H-bond energy change of MmpL3 after S288T mutation. In addition, the WT_SQ109 complex structure was obtained by molecular docking program (Autodock 4.2); Molecular Mechanics/ Poisson Boltzmann Surface Area (MM-PBSA) and Solvated Interaction Energy (SIE) methods were used to calculate the binding free energies (∆ G bind ); Geometric criteria were used to analyze the changes of hydrogen bond networks.