Potential folding-function interrelationship in proteins.

Abstract

The possibility is addressed that protein folding and function may be related via regions that are critical for both folding and function. This approach is based on the building blocks folding model that describes protein folding as binding events of conformationally fluctuating building blocks. Within these, we identify building block fragments that are critical for achieving the native fold. A library of such critical building blocks (CBBs) is constructed. Then, it is asked whether the functionally important residues fall in these CBB fragments. We find that for over two-thirds of the proteins in our library with available functional information, the catalytic or binding site residues lie within the CBB regions. From the evolutionary standpoint, a folding-function relationship is advantageous, since the need to guard against mutations is limited to one region. Furthermore, conformationally similar CBBs are found in globally unrelated proteins with different functions. Hence, substituting CBBs may lead to designed proteins with altered functions. We further find that the CBBs in our library are conformationally unstable.