DFT Study of the [Cu-Angiotensin II] 2+ Complex Structure

Angiotensin II (Ang II, an octapeptide hormone: Asp1Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) has been studied for several decades in investigations of the structure-dependent activity of the renin-angiotensin blood pressure regulation system. Metal ion influences on the biological activity of Ang II have also been investigated. Blood pressure was observed to increase as a result of the influence of Li, Na, Mg, and Ca ions on the renin-angiotensin system. Thus, it was proposed that the alkali (or alkaline-earth) metal ions induced conformational changes in Ang II that led to a conformational structure more suitable for the biological activity of Ang II. However, the Cu ion was observed to reduce blood pressure in a study performed by separate research group. A few different positive ion complexes [Cu-Ang II] have been studied. The Cu binding sites of the [Cu-Ang II] complex were suggested to have a Cu-NNNN geometry in the ATCUN (Amino Terminal Cu(II) and Ni(II)) complex. However, the Cu binding sites in the [Cu-Ang II] complex were suggested to be the oxygen atoms of the carbonyl functional groups. The structure of Ang II has been reported to be S-shaped according to the results of an NMR experiment. This S-shaped structure has two potential metal ion binding pockets (Fig. 1). Different patterns of interaction between metal ions (Mg, Cu, and Ni) and Ang II have been reported as a result of the different fragmentation patterns obtained in an electrospray ionization mass spectrometry (ESI-MS) experiment. The Mg ion was reported to choose the ‘B’ binding pocket (Ile5His6-Pro7-Phe8) in the [Mg-Ang II] complex. However, Cu and Ni ions were reported to choose the ‘A’ binding pocket (Asp1-Arg2-Val3-Tyr4) in the [Cu (or Ni)-Ang II] complexes. The metal ion binding sites of Ang II were reported to be the amide oxygen atoms instead of the deprotonated peptide nitrogen atoms (N−). In the gas phase, the ligand affinities of alkaline earth metal and transition metal ions have been reported based on the results of a collision-induced dissociation (CID) experiment using ESIMS measurement. The present paper focuses on the interaction between a Cu ion and the ‘A’ pocket of the Ang II molecule. The interaction between a Cu ion and the carbonyl oxygen atoms of Ang II is studied in terms of optimized structures obtained from ab initio calculations. The ab initio calculations were performed to determine both the optimized structures and the SCF energies of the [Cu-Ang II] complex. These optimized structures and their SCF energies are reported.