Anomalous orientation-dependent effective pair interaction among histidine and other amino acid residues in metalloproteins: breakdown of the hydropathy scale index.

Hydropathy scale is widely used to obtain a measure of the effective interaction between any two amino acid residues in proteins and is based on the assumption that attraction between two hydrophobic groups and repulsion between hydrophilic groups (in water) can be translated straightforwardly to protein environment. Here we employ a recently developed statistical mechanical approach combined with the Protein Data Bank to obtain both distance- and orientation-dependent potential of mean force (ODPMF). This allowed us to explore effective pair potential among many amino acid residues and to examine the validity of the hydropathy scale in modeling the interaction among amino acid residues. We find that in some cases, like Phe-Phe and Lys-Lys, the hydropathy scale approach is largely obeyed. However, we also observe many unexpected pair interactions which defy the trend given by published hydropathy scales. An example of the former is the arginine-arginine (Arg-Arg) pair interaction which is found to be strongly and surprisingly attractive at short separation, even though it is the most hydrophilic residue. Here the head-to-head (see text) interaction is also stabilized. Tryptophan residues also exhibit strong attractive interaction. Equally important, we find strong influence of metal in determining effective interaction among the amino acid residues. It is the behavior of the histidine (His) which is found to be the most unusual. It exhibits a strong attractive interaction with itself which gets significantly enhanced in metalloproteins. These results highlight the important (sometime hidden) role of metals in protein structure and folding.