Revisiting a dogma: the effect of volume exclusion in molecular crowding

We critically re-examined the mechanisms that affect protein stability under crowding conditions. Much attention has been paid in recent years to the effects of molecular crowding on the properties of proteins in the cellular milieu. It has been suggested that volume exclusion disfavors the unfolded state since this is more expanded than the folded one, leading to an overall stabilizing effect. Experimental results suggest however that the influence of crowding on protein stability is smaller than expected. Besides, crowding can in some cases destabilize proteins. Destabilization has been attributed to weak interactions of crowders with the protein under study. We argue against these dogmas that overemphasizing the effect of volume expansion or the role of soft interactions may mask the actual relevance of volume exclusion.