MD-DFT Computational Studies on the Mechanistic and Conformational Parameters for the Chemoselective Tyrosine Residue Reactions of G-Protein-Coupled Receptor Peptides with [Cp*Rh(H2O)3](OTf)2in Water To Form Their [(η6-Cp*Rh-Tyr#)-GPCR peptide]2+Complexes: Noncovalent H-Bonding Interactions, Molecular Orbital Analysis, Thermodynamics, and Lowest Energy Conformations

Bioconjugation of important G-protein-coupled receptor (GPCR) peptides with organometallic aqua complexes has proven to be an exciting new approach for discovering potential drugs acting on their respective GPCR receptors. Thus, in this study, we report on the mechanistic and conformational aspects for the chemoselective reactions of tyrosine-containing GPCR peptides with [Cp*Rh(H2O)3](OTf)2, in water, at room temperature (J. Am. Chem. Soc. 2012, 134, 10324). We have focused on three critically important GPCR peptides; namely, [Tyr1]-Leu-enkephalin (1), [Tyr4]- neurotensin(8–13) (2), and [Tyr3]-octreotide (3), each having a different position for the tyrosine residue, together with competing functionalities. The e-donating effect of the tyrosine phenol OH group was assumed to have provided high chemoselectivity. Therefore, we have concentrated on the important mechanistic and conformational pathways to the chemoselective tyrosine products, the [(η6-Cp*Rh-Tyr1,4,3)-GPCR peptide](OTf)2 complexes, utilizing molecular dynamics (MD) and density functional theory (DFT) methods, and have provided a mechanistic rationale for these chemoselective reactions, including noncovalent interactions, molecular orbital analysis, and thermodynamics. Furthermore, the influence of the [Cp*Rh]2+ group on the lowest energy conformations for the structures of [(η6-Cp*Rh-Tyr1)-Leu-enkephalin](OTf)2, 4, [(η6-Cp*Rh-Tyr4)-neurotensin(8–13)](OTf)2, 5, and [(η6-Cp*Rh-Tyr3)-octreotide](OTf)2, 6, were also assessed, including the essential intramolecular, noncovalent interactions that determined the lowest energy conformations of [(η6-Cp*Rh-Tyr1,4,3) GPCR peptide]2+ complexes, 4–6, in comparison to their ligands, GPCR peptides, 1–3. This represented, to our knowledge, the first MD/DFT study on mechanisms of an organometallic aqua complex reacting in an aqueous media with GPCR peptides, while also determining the critical secondary forces; for example, intramolecular, noncovalent H-bonding interactions that further defined the most stable conformations of the GPCR peptides and those of their [(η6-Cp*Rh-Tyr1,4,3) GPCR peptide]2+ complexes.