Abstract
MlaC is involved in the transportation of phospholipids between the inner and outer membranes of Gram-negative bacteria. This MlaC-mediated transport safeguards the outer membrane asymmetry thereby preserving its integrity and shielding effect against antibiotics, detergents, etc. MlaC is constituted by two domains, viz. nuclear transport factor 2-like and phospholipid-binding protein. These unique structural properties contribute to a novel ligand binding process and a diverse conformational landscape, which still remains a marginally investigated subject. In order to fill this knowledge gap, comprehensive molecular docking and simulation studies were performed. The docking experiments performed using these structures against different phospholipids reveal, for the first time, their preference for certain substrate sizes and organizations of binding planes. The conformational dynamicity of MlaC was studied by simulation using 13 different systems in different liganded states for 1000 ns each. A distinct behavioural pattern was observed between the apo open and holo open states, with the former being conformationally more flexible. A time-dependent study of the changes in binding-pocket volume further substantiated the differences in the protein dynamics. The study further aided in the identification of global and local movements, paving the path for the investigation of coordinated motions. The extensive analyses performed on different liganded systems disclose (anti-)correlated motions that have helped in the understanding of the motions and enigmatic conformational landscape of MlaC. Further, an unanticipated MlaC crystal state that further adds to the understanding of MlaC flexibility.