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)₂ in 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.将重要的G蛋白偶联受体（G-protein-coupled receptor, GPCR）肽与有机金属水络合物进行生物偶联，已被证明是发现作用于对应GPCR靶点的潜在药物的极具前景的新策略。因此，本研究针对含酪氨酸的GPCR肽与[Cp*Rh(H₂O)₃](OTf)₂在室温水溶液中的化学选择性反应，报道其机理与构象相关研究（J. Am. Chem. Soc. 2012, 134, 10324）。我们聚焦于三类至关重要的GPCR肽：分别是酪氨酸残基位置各异且带有竞争官能团的[Tyr¹]-亮氨酸脑啡肽（1）、[Tyr⁴]-神经降压素(8–13)（2）以及[Tyr³]-奥曲肽（3）。研究推测酪氨酸酚羟基的给电子效应赋予了该反应优异的化学选择性。为此，我们借助分子动力学（molecular dynamics, MD）与密度泛函理论（density functional theory, DFT）方法，深入探究了生成化学选择性酪氨酸产物[(η⁶-Cp*Rh-Tyr¹,⁴,³)-GPCR肽](OTf)₂的关键机理与构象路径，并为该类化学选择性反应提供了机理解释，包括非共价相互作用、分子轨道分析以及热力学分析。此外，我们还评估了[Cp*Rh]²⁺基团对[(η⁶-Cp*Rh-Tyr¹)-亮氨酸脑啡肽](OTf)₂（4）、[(η⁶-Cp*Rh-Tyr⁴)-神经降压素(8–13)](OTf)₂（5）以及[(η⁶-Cp*Rh-Tyr³)-奥曲肽](OTf)₂（6）这三种配合物最低能量构象的影响，并对比其配体（即GPCR肽1–3），分析了决定[(η⁶-Cp*Rh-Tyr¹,⁴,³)-GPCR肽]²⁺配合物4–6最低能量构象的关键分子内非共价相互作用。据我们所知，本研究是首个针对有机金属水络合物在水介质中与GPCR肽反应的机理开展的MD/DFT研究，同时还明确了关键的次级作用力——例如分子内非共价氢键相互作用——进一步界定了GPCR肽及其[(η⁶-Cp*Rh-Tyr¹,⁴,³)-GPCR肽]²⁺配合物的最稳定构象。