What is a desirable statistical energy function for proteins and how can it be obtained?

Can one obtain a physical energy function for proteins from statistical analysis of protein structures? A direct answer to this question is likely "no." Aless demanding question is whether one can produce a statistical energy function that has the desirable features of a physical-based energy function. Such a desirable energy function would be founded on a physical basis with few or no adjustable parameters, reproduce the known physical characters of amino acid residues, be mostly database independent and transferable, and, more importantly, reasonably accurate in various applications. In this review, we show how such a desirable energy function can be obtained via introducing a simple physical-based reference state called DFIRE (Distance-scaled, Finite, Ideal-gas REference state).