Quantum Mechanical Studies of Structure and Reactivity of Peptides Containing Tetrahydrofuran and Furan Amino Acids and Conformational Behavior of and#946; 2 3 and and#946; 3 Substituted Proline derived Peptides

Abstract

In the present work, ab initio and density functional theory calculations are employed to compare the ability of various hybrid GGA density functional and dispersion corrected functionals in exploring structural, reactivity and electronic properties of newly synthesized linear and cyclic peptides. Using B3LYP functional, we have studied the properties of terminally blocked linear tripeptide containing TAA, Boc-TAA-Leu-Val-OMe. The calculations on reaction of peptide bond formation between Boc-TAA and Leu-Val-OMe suggest that PBE0 functional reduces the electronic energy barrier heights by about 5 to 10 kcal/mol as compared to that measured by B3LYP. Computational studies on cyclization of the linear tripeptides containing (2S,5R)-cis-TAA and (2S,5S)-trans-TAA show preferential intermolecular cyclization over intramolecular cyclization of the tripeptides. The calculations using the functional, M06-2X show low barrier heights compared to that predicted by the functional, B3LYP. Using B3LYP/6-31G(d,p) and M06/6-31G(d,p) levels of theory, we have investigated homo versus heterochiral cyclic trimerization of 5-(aminoethyl)-2-furancarboxylic acid in gas phase, implicit and explicit solvent phases. The B3LYP calculations on solvent assisted structures show only thermodynamic favorability for heterochiral cyclic peptide. On the other hand, M06 calculations on the systems reveal both thermodynamic and kinetic preferences for the heterochiral cyclic tripeptide, compared to its homochiral counterpart. The study on another class of synthetic amino acids, i. e, and#946; 2,3 -, and and#946;3 - substituted homoproline reveals that structure and energetic inferences obtained from B97D and M06-2X functionals agree well with experimental results. The study suggests that PBE0 functional and dispersion corrected functionals, M06, M06-2X and B97D provide better description for reactivity and conformational properties compared to B3LYP.