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Computer simulation and conformational study performed by NMR in solution of oligopeptides fragments of N-terminal protected ?-casomorphines.

2005
2005
Inglese
VII Convegno "Complex Systems: structure, properties, reactivity and dynamics"
13-15 Giugno 2005
Alghero
Computer simulation and conformational study performed by NMR in solution of oligopeptides fragments of N-terminal protected ?-casomorphines. Exorphines'study deriving from food proteins is of particular interest because of their opioid properties, strictly connected to their structure's features. Structure-activity relationship of linear peptides in solution is ruled by conformational effects because of the peptide's main chain flexibility. In this work it has been observed di-, tri-, tetra-peptides fragments of Nterminal protected ß-casomorphines (YPFP: ß-CM-4; YPFPG: ß-CM-5; YPFPGPI: ß-CM-7; YPFPGPIP: ß-CM-8), which are well known to be opioid receptor ligands [1]. This sequence contains different alternated Prolines that is an amino acid often used to introduce conformational restraints in peptide's main chains. NH O R O N O NH OH Boc R=-Pro (ß-casomorphine-4); -ProGly (ß-casomorphine-5); -ProGlyProIle (ß-casomorphine-7); - ProGlyProIlePro (ß-casomorphine-8). The common structural feature among the studied peptides is the presence of a Tyrosine residue at the N-terminal end and the presence of another aromatic residue, the Phenylalanine, at the third position in the main chain. This is an important structural peculiarity for the coordination of the binding site of the opioid receptors. The Tyrosine hydroxide group is fundamental for the biological activity because its removal causes a total absence of activity. At the same time the proline residue at the second position is also essential for activity; its rule is to maintain the correct orientation of the Tyr and Phe side chain [2]. Besides the rotational energy barrier of the cis/trans isomerization of Proline peptide's bond is 10% lower than any other peptides bond; so on one hand the prolyl residue restricts the conformational space, on the other hand it makes possible to find both the trans and the cis isomers in solution [3]. Structural study in CHCl3 has been directed towards peptides with the following aminoacidic sequence: Boc-Tyr(tBu)1-Pro2-OMe, Boc-Tyr(tBu)1-Pro2- Phe3-OMe, Boc-Tyr1-Pro2-Phe3-Pro4-OMe. These products have been synthesized, purified and then analyzed by NMR spectroscopy, employing both mono- and bi- dimensional, homo- and hetero-nuclear correlation 1H-1H e 1H-13C techniques through which it is possible to obtain structural and conformational informations to use as constraints in molecular simulation experiments. The computer simulation has been carried on using the mixed mode MC/SD, alterning MonteCarlo steps to Stochastic Dynamics steps [4]. This way it has been obtained a series of structures and, among them, it has been extracted only ones that meet a certain criterion of selection we have imposed. Moreover we made a comparison between the results coming from the numerical simulation performed with and without constraints, finding out that this method offers promising evidences to be developed. [1] Teschemacher, H. Koch, G. Brantl, Biopolymer, 43, (1997), 99. [2] KJ. Chang, A. Killian, E. Hazum & P. Cuatrecasas, Science, 212, (1981), 75-77 [3] D. Kern, M. Schutkowski and T. Drakenberg, J. Am. Chem. Soc., 119, (1997), 8403-8408. [4] Guarnieri F., Still W. C., 1994, J. Comput. Chem., Vol.15, No.11, (1994), 1302- 1310.
none
info:eu-repo/semantics/conferenceObject
Fenude, E SDedola; Fais, M
275
04 Contributo in convegno::04.03 Poster in Atti di convegno
2
04.03 Poster in Atti di convegno
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/15578
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