Effects of Side-Chain Orientation on the Backbone Conformation of the Dehydrophenylalanine Residue. Theoretical and X-ray Study

Abstract

Two E isomers of α,β-dehydro-phenylalanine, Ac-(E)-ΔPhe-NHMe (1a) and Ac-(E)-ΔPhe-NMe(2) (2a), have been synthesized and their low temperature structures determined by single-crystal X-ray diffraction. A systematic theoretical analysis was performed on these molecules and their Z isomers (1b and 2b). The ϕ,ψ potential energy surfaces were calculated at the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels in the gas phase and at the B3LYP/6-31+G(d,p) level in the chloroform and water solutions with the SCRF-PCM method. All minima were fully optimized by the MP2 and DFT methods, and their relative stabilities were analyzed in terms of π-conjugation, internal H-bonds, and dipole-dipole interactions between carbonyl groups. The results indicate that all the studied compounds can adopt the conformation H (ϕ, ψ ≈ ±40°, ∓120°) which is atypical for standard amino acids residues. A different arrangement of the side chain in the E and Z isomers causes them to have different conformational preferences. In the presence of a polar solvent both Z isomers of ΔPhe (1b and 2b) are found to adopt the 3(10)-helical conformation (left- and right-handed are equally likely). On the other hand, this conformation is not accessible or highly energetic for E isomers of ΔPhe (1a and 2a). Those isomers have an intrinsic inclination to have an extended conformation. The conformational space of the Z isomers is much more restricted than that of the E derivative both in the gas phase and in solution. In the gas phase the E isomers of ΔPhe have lower energies than the Z ones, but in the aqueous solution the energy order is reversed.

Toward engineering efficient peptidomimetics. Screening conformational landscape of two modified dehydroaminoacids

“…54 In both dipeptide models studied in this article, N-methylation of C-terminal amide bond prevents 1 4 H-bond formation and in the case of isomer Z significantly diminish b-turn tendency. In chloroform environment, the two lowest energy structures B*C and C*H are the same as in the gas phase.…”

“…A similar effect of helix conformation induced by solvent was recently calculated for Ac-(Z)-DPhe-NMe 2 . 54 In both dipeptide models studied in this article, N-methylation of C-terminal amide bond prevents 1 4 H-bond formation and in the case of isomer Z significantly diminish b-turn tendency. This was observed in spite of the fact that Gly in i11 position is a strong b-turn inducer.…”

“…The obtained theoretical structures were classified as b-turns using the s and d values as selection criteria. Recently, we reported that the model Ac-(E)-DPhe-NMe 2 diamide, 54 both in the gas phase and in solution, adopts only two different conformations of comparable energy; the extended conformer E (/, w ffi 2175 , 130 ) and the conformer H (/, w ffi 240 , 116 ). Table I presents the selected conformational parameters and relative energies obtained at the B3LYP/6-31111G(d,p) level of theory for fully optimized conformers of Boc-Gly-(E)-DPhe-NMe 2 in the gas phase and immersed in a polarizable continuum, whose dielectric constant matches that of chloroform.…”

“…Relative energies obtained by single point calculations with M06-2X and MP2 methods on B3LYP geometries are also presented in the last two columns of Table I. Recently, we reported that the model Ac-(E)-DPhe-NMe 2 diamide, 54 both in the gas phase and in solution, adopts only two different conformations of comparable energy; the extended conformer E (/, w ffi 2175 , 130 ) and the conformer H (/, w ffi 240 , 116 ). Similarly, in larger system of model dipeptide Ac-Gly-(E)-DPhe-NMe 2 , the (E)-DPhe residue in (E)-DPhe-NMe 2 fragment adopts only two, mentioned above conformations.…”

Estimating the carbonyl anharmonic vibrational frequency from affordable harmonic frequency calculations

“…The proposed model molecules are α,β-dehydrophenylalanine derivatives and belong to a group of nonstandard peptides with a double bond between the C α and C β atoms. The α,β-dehydroamino acids have unique conformational properties and form the subject of our recent studies [33,34].…”