Physicochemical approach to cellular function and evolution.

Using live-cell NMR, first-principle theory and physicochemical proteome screening, we have distinguished a second level of generic protein-protein interactions, providing a new perspective on cellular function and evolution. Their role is to maintain the cytosolic components ‘suitably fluid’ through electrostatic repulsion.

Consistently, the hypervariable protein surfaces that promote this repulsion are under detailed evolutionary control and show divergent optimisations across all organisms.

The most remarkable aspect of this finding is not that the ‘non conserved’ regions of the genomes comprise a so far uncharted dimension of functional information, but that it challenges our understanding of the in-vivo conditions.

Instead of just presenting crowding, the ‘non-functional’ protein surfaces actively control cellular function, and this control renders the in-vivo environment more different from standard in-vitro buffer than previously anticipated.

We propose here to (i) determine how the divergent charge optimisations control some key physiological processes with already well characterised in-vitro behaviour, and to (ii) establish the limits of this control in organisms at the very extremes of the physicochemical adaptation range.As such, our work aims, beyond the function of specific genes, to the yet poorly understood role of global proteome features, to find out whether there are even deeper layers in the physicochemical optimisation of organisms waiting to be uncovered.