Proteins activity critically depends on the delicate relationship between structural stability, flexibility and function. Experimentally, the development of single-molecule force-spectroscopy techniques over the last 20 years has allowed to manipulate and to study biomolecules with outstanding accuracy. Force is used as a probe to get insights into the molecular details of macromolecular phenomena (folding, protein-protein recognition, enzymatic reactions, etc.), but it is also used in the experiments to reproduce some of the<i> in vivo</i> situations where proteins are under mechanical stress, including e.g. proteins involved in muscle elasticity. But as powerful as they might be, these techniques greatly benefit from the perspective brought by theory and molecular modelling that help guide and confirm the interpretation of experimental results.<br/><br/>In this presentation, I will discuss some very recent results on how biomolecular simulations were instrumental in unveiling the unusual force unfolding patterns of a metalloprotein. I will also discuss the main differences between protein thermal and mechanical stabilities, which will be illustrated on protein homologs from species that grow at very different temperatures. I will show that, for homologs whose structures are very similar, an increased thermal resistance is not associated with an increased mechanical stability: while we can reproduce the experimental thermal stability gap between the two proteins with enhanced sampling simulation techniques, we prove that both offer only moderate resistance to mechanical force. Our approach provides microscopic insights that are otherwise inaccessible to experimental techniques and allows to identify the protein "weak" spots for mechanical and thermal unfolding, which are found to be distinct.

Stretching or heating proteins: Unravelling the molecular details of protein resistance to external perturbations

255th National Meeting (2018)

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