TCBG Seminar

Deciphering the molecular origins of ultrastability in staph adhesins: challenges and limitations of in-silico force spectroscopy in the era of exascale computing.

Assistant Professor Rafael Bernardi
Department of Phyics
Auburn University
Auburn, Alabama

Monday, July 18, 2022
3:00 pm (CT)
Hybrid webinar recording


Mechanoactive proteins are essential for a myriad of physiological and pathological processes. Guided by the advances in single-molecule force spectroscopy (SMFS), we have reached a molecular-level understanding of how several mechanoactive proteins respond to mechanical forces. However, even SMFS has its limitations, including the lack of detailed structural information during force-loading experiments. That is where molecular dynamics (MD) methods shine, bringing atomistic details with femtosecond time-resolution. Here, we employed an in silico SMFS approach to investigate how Staphylococci adhesins form ultrastable protein complexes with proteins of the human extracellular matrix. Using a combination of bioinformatics and AI-based structure prediction methods, we obtained the structure of nearly 200 proteins of the bacterial adhesin superfamily. Then, we analyzed the mechanical properties of all these proteins using a high-throughput steered MD approach. Our results reveal that adhesins from methicillin resistant S. aureus strains are more resilient to shear forces than those of methicillin susceptible strains. Combining a myriad of state-of-the- art computational biology approaches we show that, although methicillin does not act on the adhesins, the methicillin resistant S. aureus (MRSA) strains have mutations on these proteins that give them extreme mechanostability. In fact, the complex formed between adhesins and proteins of the human extracellular matrix are the strongest protein interactions known, surpassing by an order of magnitude the strength of streptavidin-biotin. In addition, simulations were used to highlight mutations that might be associated with the increasing force resilience in methicillin resistant strains. In summary, the extreme mechanostability of all strains with a pattern of higher forces for the resistance strains was observed. With increasing prevalence of multidrug resistant bacterial infections, this new finding could be exploited for the development of antiadhesion strategies as an innovative alternative to antibiotics.

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