Proceedings book download - 5Z.com

Fig. 1. Average IR and VCD spectra of structures shown on the side, calculated in vacuum(short dashed) and in explicit D 2 O (long dashed), and experimental spectra of peptide 1recorded in D 2 O (continuous line).simple negative lobe in 50% (v/v) TFE-D 2 O mixture and strongly negatively biased inother solvents. Such simple negative amide I' VCD signal was obtained for 9 in allsolvents. For peptide 3, more complex, markedly different VCD spectra were measured inthe amide I' region. Furthermore, VCD spectra of this peptide demonstrated strongdependence on the solvent environment. This may be attributed to the high diversity of thesolution conformational ensemble of this peptide as indicated by previous MD simulations.In summary, no striking spectral characteristics were found which could be correlated to aspecial structural component and hence μ-opioid activity. This suggests that suchcomponents could only be determined via the deconvolution of VCD spectra. The IR andVCD spectra of 37 representative structures of peptide 1, identified by previous MDsimulations, was computed on the B3LYP/6-31G(d) level of theory. Inspection of theresultant prototypical spectra revealed that the following structures result in IR and VCDspectra similar to the ones observed experimentally: random meander, bent structure withno specific hydrogen bond or backbone dihedral angle values to define a β-turn, classicγ-turn around Trp 3 and C-terminal β-turn (Figure 1 A, B, C and D, respectively). A simpleaverage of spectra computed for these structures in both vacuum and explicit D 2 Omolecules is shown on Figure 1 together with the experimental spectra. Clearly, constructsof spectra calculated in solvent environment show better agreement with experimentalresults. However, much better results could be obtained if the exact contribution of eachcomponent were known. Despite the fair agreement between theoretical and experimentalspectra, the determination of the exact contribution of each conformational state remains achallenge. It is most likely, that the improvement of theoretical conformational analysiswould facilitate the achievement of such accuracy and yield a powerful method for solutionconformational analysis of short peptides, which could help to identify correlation betweenstructure and biological activity.AcknowledgmentsThis work was supported by Hungarian OTKA PD-73081 (A. Borics) and NIH-INBRE P20 RR016469(S. Lovas) grants.References1. Leitgeb, B. Chem. Biodivers. 4, 2703-2724 (2007).2. Keresztes, A., et al. Chem. Med. Chem. 5, 1176-1196 (2010).3. Keresztes, A., et al. J. Med. Chem. 51, 4270-4279 (2008).4. Tömböly, Cs., et al. J. Med. Chem. 51, 173-177 (2008).5. Borics, A., et al. J. Mol. Graph Model 28, 495-505 (2010).6. Dukor, R.K., et al. Biopolymers 31, 1747-1761 (1991).7. Borics, A., et al. Protein Pept. Lett. 14, 353-359 (2007).443