Conformational preferences and structural characterization of prolyl cis/trans isomerization of carbohydrate-templated proline mimetics of some model peptides using computational methods

Over the years a number of proline analogues have been developed to study the structural and biological properties of proline surrogates in peptides. This is due to the fact that the prolyl N-terminal cis/trans isomerization rate and equilibrium ratios of specific proline analogues are helpful in detecting and monitoring the local structure and environment of proline. Although these analogues have proven to be useful for inducing specific constraints on prolyl N-terminal amide isomerization, but lacks the ability to shift the prolyl amide equilibrium into both directions. In this study a computational analysis on some novel carbohydrate-templated proline mimetics model peptides were performed, in order to determine the effect of the carbohydrate moiety incorporation onto the proline based peptides. An extensive conformational analysis of these model peptides demonstrated that the carbohydrate moiety influences the cis/trans ratio and kinetics of the isomerization reaction.In addition, a reliable computational protocol was developed for the computational calculations of these model peptides and ha the results produced using this protocol were in excel1ent agreement with the experimental data. Final1y, this quantum mechanical study of the sugar proline analogues in addition to the extensive experimental data gave us a further insight and trend into prediction of the conformational equilibria and kinetics of the carbohydrate-templated proline-based peptidomimetics.A detailed Density Functional Theory analysis of these model peptides in water predicts that the stability of the cis population of Compound 1 and Compound 2 depends on the orientation or position of the C delta-hydroxy-methylene substituent. Results on the structural characterization also show that the intramolecular hydrogen bond influences the cis/trans isomerization ratio. The puckering amplitude calculated for both Compound I and Compound 2 shows that the position of the C delta primary hydroxyl group greatly distorts, in particular for Compound 2, the puckering behaviour of the five-membered ring, which is a key parameter in collagen stabilization.