H reversible F displacement on the phe-phenyl benzene ring in the thrombin receptor-tethered ligand peptide for elucidation of the receptor activation mechanism

摘要

Phenylalanine (Phe), an aromatic amino acid, is often crucially important in biologically active peptides to elicit intrinsic activity, and on that occasion, the side-chain phenyl group plays an essential role in the ligand-receptor interaction. Despite such an important role of Phe, the molecular mechanism of the residue, particularly its benzene ring in the side chain, has not been elucidated in detail in the ligand-receptor interaction. When Phe interacts with the alkyl side chains of amino acids Leu, Ile, Val, or Ala, the Phe-phenyl π system would function as a hydrogen acceptor. This interaction is denoted as CH/π interaction, the concept of which has recently been established by Nishio et al.. When Phe interacts with aromatic amino acids such as Phe, Tyr, Trp, and His, Phe-phenyl should be involved in two different types of π-π interactions, i.e., the face-to-face π-π stacking interaction and the edge-to-face CH/π interaction. To better understand the molecular mechanism of peptide interactions involving the Phe residue, differentiation of these Phe-phenyl π interactions is requisite. We have postulated that these π-π interactions can apparently be distinguished by replacing fluorophenylalanines for the Phe residue. Fluorine can substitute the benzene hydrogens (CHs) without changing the atomic size, and thus it is highly likely that multiple fluorine replacements of benzene hydrogens could clarify whether essential hydrogens exist on Phe-phenyl or whether the π system is required for the interaction with the receptor.