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Rate limiting step of the allosteric activation of the bacterial adhesin FimH investigated by molecular dynamics simulations
  • Gianluca Interlandi
Gianluca Interlandi
University of Washington Department of Bioengineering

Corresponding Author:[email protected]

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The bacterial adhesin FimH is a model for the study of protein allostery because its structure has been resolved in multiple configurations, including the active and the inactive state. FimH consists of a pilin domain (PD) that anchors it to the rest of the fimbria and an allosterically regulated lectin domain (LD) that binds mannose on the surface of infected cells. Under normal conditions, the two domains are docked to each other and LD binds mannose weakly. However, in the presence of tensile force generated by shear the domains separate and conformational changes propagate across LD resulting in a stronger bond to mannose. Recently, the crystallographic structure of a variant of FimH has been resolved, called FimH FocH, where PD contains 10 mutations near the inter-domain interface. Although the X-ray structures of FimH and FimH FocH are almost identical, experimental evidence shows that FimH FocH is activated even in the absence of shear. Here, molecular dynamics simulations combined with the Jarzinski equality were used to investigate the discrepancy between the crystallographic structures and the functional assays. The results indicate that the free energy barrier of the unbinding process between LD and PD is drastically reduced in FimH FocH. Rupture of an inter-domain hydrogen bond involving R166 constitutes a rate limiting step of the domains separation process and occurs more readily in FimH FocH than FimH. In conclusion, the mutations in FimH FocH shift the equilibrium towards an equal occupancy of bound and unbound states for LD and PD by reducing a rate limiting step.
27 Jan 2023Submitted to PROTEINS: Structure, Function, and Bioinformatics
27 Jan 2023Submission Checks Completed
27 Jan 2023Assigned to Editor
27 Jan 2023Review(s) Completed, Editorial Evaluation Pending
03 Feb 2023Reviewer(s) Assigned
23 Feb 2023Editorial Decision: Revise Major
17 Jul 20231st Revision Received
17 Jul 2023Assigned to Editor
17 Jul 2023Submission Checks Completed
17 Jul 2023Review(s) Completed, Editorial Evaluation Pending
17 Jul 2023Reviewer(s) Assigned
02 Aug 2023Editorial Decision: Revise Minor
04 Aug 20232nd Revision Received
05 Aug 2023Assigned to Editor
05 Aug 2023Submission Checks Completed
05 Aug 2023Review(s) Completed, Editorial Evaluation Pending
24 Aug 2023Editorial Decision: Accept