The fifth sense of a protein: Quinary interactions in SOD1

The interior of living cells is an eXtremely crowded environment, with a large part of the volume being occupied by diverse macromolecules. For a protein it is like to move in a suburban train at rush hour! However, how this crowding affects the life of a protein, in particular its stability, is still unknown. The group of our collaborator (S. Ebbinghaus at the TU in Braunschweig, Germany) using rapid laser-induced temperature jumps, showed that weak transient interactions with the surrounding macromolecules, often referred to as quinary interactions (aka the fifth order of structural organization of a protein), can indeed amplify and even reverse the stability response of proteins to single-point mutations. By performing innovative multi-scale molecular simulations we shed light on the microscopic origin of those interactions, providing a possible explanation of the experimentally observed stability effects. Together, the results highlight the importance of considering weak transient interactions with the intracellular environment when investigating the relationship between stability and function in vivo as well as possible pathogenic misfolding and aggregation paths. The work is published in JACS, see here.