Chain conformation in polyretropeptides III: Design of a 310 helix using α,α-dialkylated amino acids and retropeptide bonds

Abstract

Computer simulations have been used to design a polypeptide with a 3(10) helix conformation. The study has been been performed taking advantage of the intrinsic helix forming tendency of alpha-Aminoisobutyric acid. In order to avoid the formation of the alpha helix, which is the other common helical conformation adopted by alpha-Aminoisobutyric acid-based peptides, retropeptide bonds have been included in the sequence. Thus, retropeptides are not able to form the intramolecular hydrogen bonding interactions characteristic of the alpha helix. The influences of both the peptide length and the solvent have been examined and compared with those of the polypeptide without retropeptide bonds.

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

“…Interestingly, according to energy calculations: (a) poly[Aib(t)] n (Figure 1) adopts a poly(Gly) n type II helical structure (ϕ = ± 60°, ψ = ∓ 140°) with the CS and NH groups perpendicular to the helix axis (pointing away from and toward the helix axis, respectively),60 and (b) an (rAib) n retropeptide sequence (Figure 1) can fold into a 3 10 ‐helix, but not into an α‐helix 61. However, to our knowledge, no experiments have been performed to date to corroborate these theoretical findings.…”

Integrating the intrinsic conformational preferences of noncoded α‐amino acids modified at the peptide bond into the noncoded amino acids database

“…Reversal of the peptide bond has been used for designing bioactive pseudopeptides,49–53 for engineering and mirroring protein secondary structural motifs,54–57 and for the construction of synthetic (bio)polymers mimicking the structures found in fibrous proteins 58, 59. NCAD includes the conformational preferences of 5 diacids and 4 diamines (Table II) that are surrogates of the following α‐amino acids: Gly,59, 60 Ala,59 Val,61 α‐aminoisobutyric acid (Aib), and dehydroalanine63 (ΔAla).…”

“…In an earlier work, we used retropeptide bonds to enhance the stability of the 3 10 ‐helix with respect to the α‐helix in peptides containing Aib 69. Specifically, Aib‐containing homoretropeptides (hereafter denoted r Aib‐ n , where n indicates the number of residues) cannot form the intramolecular hydrogen‐bonding network that stabilizes the α‐helix ( i ← i +4) and this results in unfavorable interactions between the CO groups of residues i and i +4.…”

Force-field parametrization of retro-inverso modified residues: Development of torsional and electrostatic parameters

“…Thus, modified amino acids are usually employed as building blocks in molecular engineering since they can be used to control the peptide secondary structure [11,12], and to design molecules with enhanced resistance to biodegradation but retaining the biological response of bioactive peptides [13,14]. Modifications may involve changes in the amino acid side chain or alteration of the amide bond.…”

“…glycine, alanine, valine and dehydroalanine, has been investigated by our group using ab initio QM methods [29][30][31][32][33]. QM calculations were also used in molecular engineering applications devoted to stabilize a given structural motif using retromodified peptides based on a-aminoisobutyric [11] and glycine [34,35]. Conformational analysis of retro-inverso modified amino acids has been also performed using simulations based on MM [36][37][38].…”