TCB Seminar

“Molecular Mechanisms of Protein Mechanostability Revealed by in silico Single Molecule Force Spectroscopy

Dr. Rafael Bernardi
Theoretical and Computational Biophysics Group
UIUC
Unknown Location

Monday, January 14, 2019
3:00 pm
3269 Beckman Institute

Abstract

Mechanical forces play a fundamental role in biological systems, where mechanically active proteins can sense and respond to force by undergoing conformational changes or modulating their function in a variety of ways. Many of these proteins are exposed to a turbulent environment, where they face shear forces that would break even some of the weaker covalent bonds. At the focus of my presentation will be the molecular mechanisms by which some protein complexes with no covalent linkage are as force resilient as covalent bonds. To investigate these mechanisms, we take advantage of molecular dynamics simulations, both at the classical and the QM/MM levels, which were analyzed using machine learning approaches and combined with single-molecule force spectroscopy experiments. The best example of these hyperstable protein complexes are found in the adhesion mechanism of staphylococcal bacteria to its human host. The interaction of the bacteria adhesion protein with human fibrinogen was found to be the mechanically strongest noncovalent protein-protein receptor-ligand interactions to date, rivaling a regime formerly exclusively associated with covalent bonds. Our joint computational-experimental approach revealed not only how strong this protein complex is, but also the molecular details that are responsible for such strength. The mechanostability of the complex only marginally depends on the fibrinogen side chains and thus on its sequence. The mechanism proposed provides an atomistic understanding of why these adhesions can adhere to their hosts so resiliently, from which possible routes to inhibit it and impede staphylococcal adhesion may be derived.