An additional analysis of electrostatic energies suggests that combinatorial dominance of the interactions between opposite charges makes the electrostatic interactions act as an unspecific folding force that stabilizes not only native structure, but also compact random conformations.
Contrary to intuition, our results suggest that side-chain–backbone interactions play the major role in side-chain packing, in stabilizing the folded structures, and in differentiating the folded structures from the unfolded or misfolded structures, while the interactions between side chains have a secondary effect. Here we present the results of a comparative analysis of the contributions of side-chain–side-chain ( s-s) and side-chain–backbone ( s-b) interactions to the stabilization of folded protein structures within the framework of the CHARMm molecular data model. This characteristic design of protein building blocks implies that side-chain–side-chain interactions play an important, even dominant role in 3D-structural realization of amino acid codes. The basic differences between the 20 natural amino acid residues are due to differences in their side-chain structures.
