HP-SEE User Forum 2012, Belgrade

Conformational Analysis of Kyotorphin Analogues Containing Unnatural Amino Acids

18 Oct 2012, 15:45

1h 15m

National Library of Serbia

Poster Computational Chemistry Poster session

Speaker

Nicolay Dodoff (Roumen Tsanev Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria)

Description

The dipeptide kyotorphin (Tyr-Arg, Kyo) plays a role in pain modulation in the mammalian central nervous system (CNS), and is one of the most investigated neuropeptides. The Tyr-Arg motif exists widely throughout the brain not only as kyotorphin, but also as the N-terminal part of several endogenous analgesic peptides1,2. Also, this peptide is very rapidly degraded by aminopeptidases3. One of the successful strategies in the design of neuropeptides with enhanced stability and improved delivery to the CNS is that with the use of non-protein amino acids, like canavanive (Cav), a structural analogue and antimetabolite of arginine (Arg). In our previous in vivo experiments we demonstrated that Tyr-Cav exerted a strong-reversible analgesic effect, more pronounced than that of Kyo. Bearing in mind these and the fact that norsulfoarginine (NsArg)4 is a structural analogue of arginine and canavanine, we synthesized a series of new peptides with expected analgesic activity, containing NsArg residues in their molecules: NsArg-Tyr, Tyr-NsArg, Tyr-NsArg-NH2 and Tyr-NsArg-OBzl5,6. The conformational features of these dipeptides are of particular interest, both from theoretical and pharmacological point of view. Since no single-crystal X-ray diffraction data for the compounds are available until now, we undertook a quantum-chemical modelling of their structure. We have undertaken a profound conformational study of kyotorphin and its synthetic analogues, containing unnatural amino acid nor-sulfoarginine (NsArg). Here we present our preliminary computational results for Kyo, NsArg-Tyr аnd Tyr-NsArg. Molecular mechanics (MM+ force field) conformational search for the two species was performed, and the global minimum-energy conformations thus obtained, were further optimized at HF ab initio (3-21G** basis set) level of theory. In the three cases (Kyo, NsArg-Tyr, and Tyr-NsArg) specific, scorpion-like conformations are realized, with hydrogen bonds involving the guanidino-group and the phenolic hydroxyl. Numerical results are obtained using HPC cluster deployed at the Institute of Information and Communication Technologies. This cluster is part of High-Performance Computing Infrastructure for South East Europe’s Research Communities.