A tale of two proteins: What folding dynamics can tell us about the function of structurally similar proteins

Protein sequences have been optimized by evolution to facilitate fast folding (folding on a biologically relevant timescale). This implies that residues selected for folding are less likely to participate in non-native stabilizing interactions. Such interactions need to be broken before native interactions are formed and this breaking and forming slows folding. Functional residues, on the other hand, have been selected for function, may not be optimal for folding, may facilitate the formation of non-native traps and slow folding. My group has been working on understanding the effect of such non-optimal functional residues on folding energy landscapes using computational models.
 
In this talk, I will present results on the folding of two structurally similar but functionally distinct proteins: monellin (a sweet protein) and stefin-B (a cysteine protease inhibitor). Despite having similar structures, we find that their sequences and in turn, the energetics of the two proteins are tuned to facilitate their differing functions and these energetic differences lead to entirely different folding characteristics. Understanding these differences computationally has led to diverse predictions which could drive the design of intrinsically disordered proteins that fold upon binding as well as protein assembly. I will also outline some experiments that support these results.