Characterization of Asx Turn Types and Their Connate Relationship with β‐Turns

Abstract

Models of asparagine‐containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn‐Ala and Asn‐Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H‐bond that was very similar to a type II’ β‐turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence‐dependent behavior. In Asn‐Ala sequences, the Asx turn was found in conjunction with a type I β‐turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II’ (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone β‐turn. In contrast, the Asx turns observed in Asn‐Gly sequences extensively adopted a type II Asx‐turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn‐Gly sequence is also often found in combination with a hydrated β‐bulge supports the premise that a Asn‐Gly sequence might efficiently promote the formation of the β‐bulge secondary structure.

Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis

“…On the contrary, a study of a database of 500 proteins found that the frequency of occurrence of Asx turn is type-Ⅱ′, while the most common type is βI turn 30 . These findiA recent study of Asx also supported these findingsn-Ala and Asn-Gly in crystallized protein structures in the PDB 31 , revealing that the most common Asx turn in these two sequences are type-Ⅱ′ and type-Ⅱ, respectively. In sum, our results suggest that azaAsn and azaAsp residues in models 4 and 5 could have different folding patterns than natural peptides and the,y could also enhance the formation of a type-Ⅰ Asx turn instead of type-Ⅱ′ mostly found in peptides.…”

“…Since Asx turns are mimicry of β turns, the dihedral angles ϕe and ψe of Asx turn (Fig. 6) should resemble those of i+1 in β turns, while ϕ and ψ of residue i+1 of Asx turns should resemble those of residue i+2 in β turns 30,31 . -80 0 Furthermore, the azaAsx-Pro chain contains another C10 pseudo-cycle similar to an Asx turn, which is related to the H.B.…”

Catalytic DxD motif caged in Asx-turn and Met–aromatic interaction attenuates the pathogenic glycosylation of SseK2/NleB2 effectors

“…However, in SseK2/NleB2 effectors, we found that the first aspartate in the DxD motif was previously intertwined with the C10 H-bond network, namely the Asx-turn (Asp/Asn-turn), which is incapable of binding Mn 2+ . Recently, Asn-containing peptide models, specifically designed to not form the β-turn, favor intrinsic folding into an Asx-turn; analysis of Asn turns in PDB proteins confirmed that the Asx-turn is the most stable innate structure before the backbone β-turn 24 . This suggests that the catalytic aspartate side-chain of the SseK2/NleB2 DxD motif caged-in Asx-turn is more tightly intertwined than the free aspartate side-chain of the fatal SseK1/3 and NleB1 DxD motifs in the backbone Type-I-turn, which prohibits the catalytic DxD motif from binding Mn 2+ and glycosylating targets.…”

Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction

“…6 Nevertheless, recent in silico research has shown that Asx−Gly sequence in a small dipeptide model is able to induce type II′ β-turns independently. 7 Since an effective approach to stabilize turn conformation is the synthesis of rigid peptide turn surrogates, we present herein the design, synthesis, and conformational analysis of novel hydantoin-based loops, where (1) the structure of Asn is embedded into a more rigid hydantoin five-membered ring, and (2) a flexible glycine or an even more flexible ethylenediamino residue is tethered to the Nα of Asn (or N1 of the hydantoin ring), respectively, in Hyd-loop I and Hyd-loop II (Figure 1, bottom). We reasoned that if a turn structure can exist in a flexible Asp−Gly sequence, even if triggered by a pre-existing β-turn, the designed hydantoin loops could possibly induce in itself a defined turn conformation with a 9-membered ring intramolecular Hbond.…”

“…To date, the debate on which turn pre-exists, thus fostering the formation of the second, is still open . Nevertheless, recent in silico research has shown that Asx–Gly sequence in a small dipeptide model is able to induce type II′ β-turns independently . Since an effective approach to stabilize turn conformation is the synthesis of rigid peptide turn surrogates, we present herein the design, synthesis, and conformational analysis of novel hydantoin-based loops, where (1) the structure of Asn is embedded into a more rigid hydantoin five-membered ring, and (2) a flexible glycine or an even more flexible ethylenediamino residue is tethered to the Nα of Asn (or N1 of the hydantoin ring), respectively, in Hyd-loop I and Hyd-loop II (Figure , bottom).…”