Molecular mechanics of Staphylococcus aureus adhesin, CNA, and the inhibition of bacterial adhesion by stretching collagen.

Ali Madani,Mohammad R K Mofrad,Kiavash Garakani,Firas H Kobeissy

doi:10.1371/journal.pone.0179601

Ali Madani, Mohammad R K Mofrad + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0179601

Copy DOI

Journal: PloS one	Publication Date: Jun 30, 2017
Citations: 42	License type: CC BY 4.0

Affiliation: University of California, Berkeley

Abstract

Bacterial adhesion to collagen, the most abundant protein in humans, is a critical step in the initiation and persistence of numerous bacterial infections. In this study, we explore the collagen binding mechanism of the multi-modular cell wall anchored collagen adhesin (CNA) in Staphylococcus aureus and examine how applied mechanical forces can modulate adhesion ability. The common structural-functional elements and domain organization of CNA are present across over 50 genera of bacteria. Through the use of molecular dynamics models and normal mode analysis, we shed light on the CNA’s structural and conformational dynamics and its interactions with collagen that lead to collagen binding. Our results suggest that the linker region, CNA165-173, acts as a hinge exhibiting bending, extensional, and torsional modes of structural flexibility and its residues are key in the interaction of the CNA-collagen complex. Steered molecular dynamics simulations were conducted with umbrella sampling. During the course of these simulations, the ‘locking’ latch from the CNA N2 domain was dissociated from its groove in the CNA N1 domain, implying the importance of the latch for effective ligand binding. Finally, we observed that the binding efficiency of the CNA N1-N2 domains to collagen decreases greatly with increasing tensile force application to the collagen peptides. Thus, CNA and similar adhesins might preferentially bind to sites in which collagen fibers are cleaved, such as in wounded, injured, or inflamed tissues, or in which the collagenous tissue is less mature. As alternative techniques for control of bacterial infection are in-demand due to the rise of bacterial antibiotic resistance, results from our computational studies with respect to the mechanoregulation of the collagen binding site may inspire new therapeutics and engineering solutions by mechanically preventing colonization and/or further pathogenesis.

Highlights

The molecular pathogenesis of bacterial infections involves several different processes and factors
Using a combination of molecular dynamics (MD) simulations with umbrella sampling and normal-mode analysis (NMA), we explore the molecular details of the Collagen Hug Model for binding mechanism [17] and examine how adhesion is modulated by stretching collagen proteins
The residue sequence of the N1-N2 collagen adhesin (CNA) domains were extracted from the crystal structure (2F6A) provided by the RCSB PDB and verified by the Uniprot database

Summary

Introduction

The molecular pathogenesis of bacterial infections involves several different processes and factors. Cell wall-anchored proteins play critical roles in the pathogenesis of infections caused by numerous bacteria. Pathogens bind to extracellular matrix (ECM) proteins, which display a variety of specific adhesion sites for bacteria and eukaryotic cells. Many bacteria have evolved cell-surface proteins that expose recognition sequences for a majority of host ECM proteins, including collagen, fibronectin (Fn), fibrinogen (Fg), and other proteins [1]. Mechanical factors have been implicated in the regulation of bacterial adhesion to the ECM. For fibronectin-binding bacterial proteins, it has been shown that stretching fibronectin fibers can disrupt bacterial adhesion. For fibronectin-binding bacterial proteins, it has been shown that stretching fibronectin fibers can disrupt bacterial adhesion. [2]

Methods

Results

Conclusion