Gating at both ends and breathing in the middle: conformational dynamics of TolC.

Journal article

Drug extrusion via efflux through a tripartite complex (an inner membrane pump, an outer membrane protein, and a periplasmic protein) is a widely used mechanism in Gram-negative bacteria. The outer membrane protein (TolC in Escherichia coli; OprM in Pseudomonas aeruginosa) forms a tunnel-like pore through the periplasmic space and the outer membrane. Molecular dynamics simulations of TolC have been performed, and are compared to simulations of Y362F/R367S mutant, and to simulations of its homolog OprM. The results reveal a complex pattern of conformation dynamics in the TolC protein. Two putative gate regions, located at either end of the protein, can be distinguished. These regions are the extracellular loops and the mouth of the periplasmic domain, respectively. The periplasmic gate has been implicated in the conformational changes leading from the closed x-ray structure to a proposed open state of TolC. Between the two gates, a peristaltic motion of the periplasmic domain is observed, which may facilitate transport of the solutes from one end of the tunnel to the other. The motions observed in the atomistic simulations are also seen in coarse-grained simulations in which the protein tertiary structure is represented by an elastic network model.

Authors: Vaccaro, L; Scott, K; Sansom, MS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Biophysical journal
• Volume: 95
• Issue: 12
• Pages: 5681-5691
• Publication date: 2008-12-01
• DOI: 10.1529/biophysj.108.136028
• EISSN: 1542-0086
• ISSN: 0006-3495
• Language: English
• Keywords: Protein Stability; Protein Structure, Tertiary; Mutation; Escherichia coli Proteins; Sequence Homology, Amino Acid; Protein Conformation; Ion Channel Gating; Escherichia coli; Phospholipids; Periplasm; Membrane Transport Proteins; Bacterial Outer Membrane Proteins; Lipid Bilayers; Principal Component Analysis; Models, Molecular