Quantum chemical investigations on intraresidue carbonyl-carbonyl contacts in aspartates of high-resolution protein structures.

The folding and stability of a polypeptide chain are due to many different and simultaneous noncovalent interactions. Recent studies have observed several novel and counterintuitive contacts in protein structures, and the nature of interactions due to such contacts is yet to be fully elucidated. We have identified carbonyl-carbonyl intraresidue contacts in 102 Asp residues from a data set of high-resolution protein structures. At the outset, it appears that such close approach of two carbonyl oxygen atoms is energetically not favorable. We have carried out ab initio quantum chemical calculations on 10 representative examples of self-contacting Asp residues from different regions of the Ramachandran map. Potential energy scan using three levels of theory (HF, B3LYP, and MP2) and two basis sets (6-31+G* and 6-31++G**) was performed by varying the side-chain dihedral angle chi(1) while keeping all other parameters corresponding to that observed in the protein structures. We also calculated interaction energies by considering the surrounding interacting residues and water molecules. Our results show that the energy difference between a self-contacting Asp residue from the crystal structures and the minimum energy conformations is about 10-15 kcal/mol. This small energy difference is compensated by its interactions with the surrounding residues and water molecules as observed in the interaction energy analysis. The results are independent of the levels of theory used. The contacting carbonyl-carbonyl groups adopt a sheared parallel motif orientation which helps to expose both the backbone and side-chain carbonyl oxygen atoms and enable them to participate in tertiary interactions. Natural bond orbital calculations indicate that carbonyl-carbonyl groups in self-contacting Asp residues interact through n --> pi* electron delocalization. The geometry analysis and nature of chemical interactions together explain the rationale for the existence of such Asp residues in protein structures and their importance in the protein stability.