- Synthesis, experimental and in silico studies of N-fluorenylmethoxycarbonyl-O-tert-butyl-Nmethyltyrosine, coupled with CSD data: A survey of interactions in the crystal structures of Fmoc amino acids
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Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc tyrosine or Fmoc phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan- 2-yl)oxy]phenyl}propanoic acid or N-fluorenylmethoxycarbonyl-O-tertbutyl-N-methyltyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047 8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H H, C H/H C and O H/H O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogenbonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C H O, C H , (fluorenyl)C H Cl(I), C Br (fluorenyl) and C I (fluorenyl) interactions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further supported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supramolecular hydrogen-bonding patterns in biocomplexes are emphasized, for the first time.
- Bojarska, Joanna,Kaczmarek, Krzysztof,Madura, Izabela D.,Remko, Milan,Wolf, Wojciech M.,Zabrocki, Janusz
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p. 328 - 345
(2020/04/20)
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- Synthesis, conformational, properties, and antibody recognition of peptides containing β-turn mimetics based on α-alkylproline derivates
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Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a β-turn conformation in aqueous solution. Two monoclonals were isolated that recognized the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala specifically at the β-turn formed by Tyr-Pro-Tyr-Asp. Peptide analogues were then synthesized containing mimetics designed to stabilize this conformation. One, analogue (3), contained a spirocyclic γ-lactam bridge between the α-position of proline-2 and the N atom of tyrosine-3, while another (2) contained (S)-α-methylproline at position 2. NMR spectroscopy and molecular modeling suggest that both analogues adopt reverse-turn conformations stablized relative to that in the native sequence. For the (S)-α-methylproline analogue binding to both monoclonal antibodies was substantially improved, compared with the native antigen, whereas the γ-lactam analogue (3) was not recognized by either antibody. Quantitative equilibrium ultrafiltration binding assays showed that the affinities of the (S)-α-methylproline analogue (2) for the two antibodies were improved over those measured with the native antigen by -2.3 and -0.65 kcal/mol. The origins of these free energy differences cannot be explained wholly on the basis of presumed extra hydrophobic contacts between the new methyl substituent and the antigen binding sites. We propose that the increased conformational stability of the analogue plays a decisive role, implying that the reverse turn detected in the native antigen, possibly a type-I turn, is important for recognition by the two antibodies.
- Hinds,Welsh,Brennand,Fisher,Glennie,Richards,Turner,Robinson
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p. 1777 - 1789
(2007/10/02)
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