BamA, the core component of the β-barrel assembly machinery (BAM) complex, is an integral outer membrane protein (OMP) in Gram-negative bacteria that catalyzes the folding and insertion of OMPs. A key feature of BamA relevant to its function is a lateral gate between its first and last β-strands. Opening of this lateral gate is one of the first steps in the asymmetric-hybrid-barrel model of BamA function. In this study, multiple hybrid-barrel folding intermediates of BamA and a substrate OMP, EspP, were constructed and simulated to better understand the model’s physical consequences. The hybrid-barrel intermediates consisted of the BamA β-barrel and its POTRA5 domain and either one, two, three, four, five, or six β-hairpins of EspP. The simulation results support an asymmetric-hybrid-barrel model in which the BamA N-terminal β-strand forms stronger interactions with the substrate OMP than the C-terminal β-strand. A consistent "B"-shaped conformation of the final folding intermediate was observed, and the shape of the substrate β-barrel within the hybrid matched the shape of the fully folded substrate. Upon further investigation, inward-facing glycines were found at sharp bends within the hybrid and fully folded β-barrels. Together, the data suggest an influence of sequence on shape of the substrate barrel throughout the OMP folding process and of the fully folded OMP.

Molecular dynamics simulations of the intermediate states of BamA folding an outer membrane protein

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