Preferential mode of cyclization of tetrahydrofuran amino acids containing peptides: some theoretical insights

Abstract

Theoretical insights have been provided for the observed preference of cyclodimerization over intramolecular cyclization reactions in linear tripeptides containing “2,5‐cis” (2S,5R)‐tetrahydrofuran amino acid as well as in those containing “2,5‐trans” (2S,5S)‐tetrahydrofuran amino acid, using quantum chemical methods. The geometries of species involved as well as the feasibility of cyclization reactions are studied at the B3LYP/6‐31G(d,p) level of theory in gas phase as well as in solvent phase. Thermodynamic data from Hessian calculations favor the intermolecular cyclization. Analysis of optimized geometries reveals the existence of additional stabilizing hydrogen bonding interactions in intermolecularly cyclized products. The existence of these second‐order interactions is substantiated by topological (atoms in molecules (AIM)) and natural bond orbital (NBO) analyses. Such interactions are absent in the intramolecular cyclization products. Further justification for the presence of stabilizing interactions in intermolecularly cyclized products comes from the molecular electrostatic potentials and electron density surfaces. Kinetic control favoring the intermolecularly cyclized products due to additional entropy of activation in the intramolecular case is surmised. Copyright © 2009 John Wiley & Sons, Ltd.

Inter- versus intra-molecular cyclization of tripeptides containing tetrahydrofuran amino acids: a density functional theory study on kinetic control

“…Indeed, at 6-311+G(d,p), 6-311++G(d,p), aug-cc-pVDZ, cc-pVTZ levels of basis set using B3LYP functional and at MP2/6-31G(d,p) level of theory, it is negative. These observations support our earlier predictions on the reactions based on B3LYP/6-31G(d,p) level of theory in the gas phase [45]. In summary, the qualitative trends of the energies of the intermediates, transition states and products in a given reaction pathway are independent of the quality of the basis set used.…”

“…Extensive NMR techniques (NOESY), classical molecular dynamics (MD), circular dichroism (CD) and mass spectrometric analyses proved this phenomenon. This led us to investigate the stabilities of the cyclic C 2 symmetric hexapeptides and cyclic tripeptides based on density functional theory (DFT) [44] calculations, and we found that cyclic hexapeptide products are thermodynamically more stable than cyclic tripeptides [45].…”

Towards the synthesis of sugar amino acid containing antimicrobial noncytotoxic CAP conjugates with gold nanoparticles and a mechanistic study of cell disruption

“…Peptides 1-4 were synthesized by cyclodimerization 7 (BocNH)-Phe-Leu] 2 , coupling with RCO-Lys(Boc)-OH and final deprotection gave the desired peptides. Peptides 1-3 were attached to the gold nanoparticles through place exchange reaction with octanethiol stabilized gold nanoparticles and the resulting conjugates could be visualized in their TEM pictures taken in MeOH and aqueous solution of peptide 1 attached nanoparticles (Fig.…”