A Computational Model for Membrane Protein Flux across the Bacterial Periplasm

Abstract

Outer membrane protein (OMP) biogenesis is critical to bacterial physiology including pathogenesis and antibiotic resistance. The process of OMP biogenesis has been thoroughly studied in vivo and each of its components have been studied in isolation in vitro. This work integrates parameters and observations from both in vivo and in vitro experiments into an integrated model. We utilize this model to computationally assess OMP biogenesis in a global manner. Using deterministic and stochastic methods we are able to simulate OMP biogenesis under several genetic conditions, each of which successfully replicates experimental observations. We observe that unfolded OMP has a prolonged lifetime in the periplasm where it makes, on average, hundreds of short-lived interactions with chaperones before folding into its native state. We find that some periplasmic chaperones function primarily as quality control factors, which complements the folding catalysis function of other chaperones. Mechanistic hypotheses proposed in the literature include either a physical bridge between the inner and outer membranes or parallel folding pathways catalyzed by different chaperones. The implementation of these mechanisms is not required to reproduce experimental results. Finally, we find a finely tuned balance between thermodynamic and kinetic parameters maximizes OMP folding flux and minimizes aggregation and unnecessary degradation. This work provides a holistic interpretation of OMP biogenesis that provides unique insight into this essential pathway.