- Staphylococcus bacteria are a leading cause of hospital-acquired infections
- Blue Waters supercomputer used to deconstruct the interaction between staph and human cells
- Discovery of extremely strong mechanical bond could lead to new design for microbial therapies
What makes pathogenic bacteria so persistent?
Researchers from the Beckman Institute at the University of Illinois and the University of Munich (LMU) are using the National Center for Supercomputing Applications' (NCSA) Blue Waters supercomputer to simulate and decipher the physical adhesion mechanism of a widespread pathogen virulence factor.
This, in turn, could lead to innovation in the treatment and prevention of relatively common staph infections that can turn deadly.
Staph infections are caused by staphylococcus bacteria, germs commonly found on the skin of healthy individuals. Most of the time, these bacteria cause few problems. However, septicemia (AKA blood poisoning) can occur when staph bacteria enter a person’s bloodstream, giving it access to locations deep within the body. Staphylococcus is the leading cause of hospital-acquired infections, frequently preying on medical devices such as artificial joints or cardiac pacemakers.
But how do these bacteria invade our bodies? Staph bacteria adhere to their human hosts with exceptional mechanical resilience. Understanding the mechanisms that underlie this persistent stickiness at the molecular level is instrumental to combat such invaders.
Combining experimental and computational approaches, Rafael Bernardi and the late Klaus Schulten from the Beckman Institute teamed up with Lukas Milles and Hermann Gaub from the LMU Physics Department to decipher the mechanism responsible for staph adhesion.
The collaborative study took advantage of NCSA’s Blue Waters supercomputer to deconstruct the interaction between staph adhesion factors and human proteins. Using an Atomic Force Microscope (AFM) the LMU team measured the forces that govern the interaction between an individual adhesin (a staph protein) and its human target molecule.
Independently, the Illinois team investigated the same protein complex by performing computationally-intensive steered molecular dynamics (SMD) simulations on Blue Waters.
The unbinding force of a single adhesin-human protein complex measured was exceptional, reaching over two nanonewtons, nearly an order of magnitude stronger than most other protein-protein interactions.
The complex was so strong that, at first, we thought something had gone wrong with the experiment. ~Lukas Milles.
How is this extreme binding force generated? The answer to what gives this system such exceptional mechanical strength can be found in its physical principle, which was revealed through the seamless integration of experimental and computational results.
"The large number of molecular dynamics simulations performed, over 2,400, allowed the team to compare simulations and experiments in the same framework," said Bernardi.
"The agreement between simulation and experiments were always good in the past, yet in a qualitative way," said Gaub. "However, the new results obtained by the Illinois team using Blue Waters allowed a direct comparison also in a quantitative manner."
Moreover, due to the incredible agreement between simulation and experiment, the Illinois researchers felt confident to test in silico experiments that could not be carried out in vitro.
Bernardi explains that systematically "turning off" different physical variables in the simulations allowed them to identify the key contributors to the large mechanical strength of the complex.
The team discovered that the interactions that make the staph adhesin so strong when binding human proteins were mediated mainly by hydrogen bond interactions between the protein backbones.
The supercomputer-created simulations revealed that, when exposed to mechanical stress, the hydrogen bonds lock in a cooperative shear geometry—the underlying physical principle.
This specific configuration is able to reach extreme forces, as all bonds have to be broken in parallel to dissociate the target. In a simplified analogy, two strips of Velcro are difficult to separate when pulled from opposing ends, yet come apart easily when pulled orthogonally.
Through site-directed mutagenesis and studies on homologs, the computational model was confirmed. This bond geometry offers a striking advantage: By confining the physics of the mechanism to the peptide backbone, which is identical for every protein, high strength can be achieved binding a large spectrum of targets.
Thus, the extreme physical strength of the system is largely independent of sequence and biochemical properties, but a built-in physical property—an invasive advantage for these staphylococci.
The unexpected mechanism expands our understanding of why pathogen adhesion is so resilient and may open new ways to inhibit staphylococcal invasion.
The development of anti-adhesion therapy could promote the detachment of staph bacteria, facilitating bacterial clearance. Understanding the mechanism of staph infection at the molecular and now atomic level may open new avenues for an intelligent design of antimicrobial therapies.