Conformational analysis of carboxylate and carboxamide side-chains bound to cations.

The known structures, both small as well as macromolecules, as stored in the respective databases, provide a wealth of information that, when properly rationalized, can be used in the design of new molecules. The engineering of metal-binding sites in proteins requires an understanding of the effect of such a binding on the ligand conformation. Here we present an analysis of the side-chain conformations of aspartic and glutamic acids, asparagine and glutamine bound to cations, in proteins. The most populated state of the chi 1 torsion angle for Asx (aspartate and asparagine) residues is g- (around 64 degrees) and is occupied by all groups that have another ligand two residues ahead of them. Co-ordinating residues that are sequentially well separated from other ligands (and most Glx (glutamate and glutamine) belong to this category) show a preference for the g+ or t state (dihedral angle near -60 and 180 degrees, respectively) as is normally observed. A chi 2 value close to, but less than 180 degrees, offers the minimum energy conformation for Glx, but another ligand closely in the sequence can force the torsion to be in a gauche form. A survey of small molecule structures involving Asx and Glx fragments show the terminal torsion to be centred at 0 degree. This observation is imitated by ligand Asx groups, whereas for Glx the angle veers towards the negative side. This statistical preference becomes less prominent when the cation is held in the less commonly observed anti geometry, and is lost completely when the residues are involved in anion binding. Cations exhibit an absolute preference to bind the oxygen that is on the same side as C alpha for the shorter side-chain, and the one eclipsing C beta for the longer chain. The shortest amino acid with a charged side-chain, Asp, shows very subtle conformational variations. For example, the distribution of chi 1 is not symmetrical about 180 degrees, and the g+ state (at -68(+/- 5) degrees) is the most stable of all on the basis of both steric as well as electrostatic grounds. Besides, the magnitude and the sign of chi 2 show strong dependence on the chi 1 values. Even for the longer Glu side-chain, a chi 2-angle in the g+ state necessitates the chi 1 also to reside in the g+ conformation. These mutual dependences of torsion angles in small molecule structures are also retained in proteins.(ABSTRACT TRUNCATED AT 400 WORDS)