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Autotransporters are a large family of virulence factors found in Gram-negative bacteria that play important roles in their pathogenesis. The passenger domain of autotransporters is almost always composed of a large β-helix, with only a small portion of it being relevant to its virulence function. This has led to the hypothesis that the folding of the β-helical structure aids the secretion of the passenger domain across the Gram-negative outer membrane. In this study, we used molecular dynamics simulations and enhanced sampling methods to investigate the stability and folding of the passenger domain of pertactin, an autotransporter from Bordetella pertussis. Specifically, we employed steered molecular dynamics to simulate the unfolding of the entire passenger domain as well as self-learning adaptive umbrella sampling to compare the energetics of folding rungs of the β-helix independently ("isolated folding") versus folding rungs on top of a previously folded rung ("vectorial folding"). Our results showed that vectorial folding is highly favorable compared with isolated folding; moreover, our simulations showed that the C-terminal rung of the β-helix is the most resistant to unfolding, in agreement with previous studies that found the C-terminal half of the passenger domain to be more stable than the N-terminal one. Overall, this study provides new insights into the folding process of an autotransporter passenger domain and its potential role in secretion across the outer membrane. Copyright © 2023 Biophysical Society. All rights reserved.

Citation

Yui Tik Pang, Anthony J Hazel, James C Gumbart. Uncovering the folding mechanism of pertactin: A comparative study of isolated and vectorial folding. Biophysical journal. 2023 Jul 25;122(14):2988-2995

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PMID: 36960532

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