Kinetic study of aza-amino acid incorporation into peptide chains: Influence of the steric effect of the side chain

Härk, Heleri Heike; Troska, Alla; Arujõe, Meeli; Burk, Peeter; Järv, Jaak; Ploom, Anu

doi:10.1016/j.tet.2022.133161

Cited by 2 publications

(3 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…azapeptides, a change in the backbone of a peptide by substituting the α-carbon with a nitrogen atom [4][5][6] . This modification confers azapeptides more resistance to physiological degradation and long duration of action 7 . Many studies revealed the importance of incorporating an azaamino acid in the peptide's sequence to enhance the stability and bioavailability of drug candidates [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

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

Khabchi¹,

Mcharfi²,

Benzakour³

et al. 2023

Preprint

View full text Add to dashboard Cite

Azapeptides have gained much attention due to their ability to enhance the stability and bioavailability of peptide drugs. Their structural preferences, essential to understanding their function and potential applica-tion in the peptide drug design, remain largely unknown. In this work, we systematically investigated the conformational preferences of three azaamino acid residues in tripeptide models, Ac-azaXaa-Pro-NHMe [Xaa= Asn (4), Asp (5), Ala (6)], using the popular DFT functionals, B3LYP and B3LYP-D3. A solvation model density (SMD) was used to mimic the solvation effect on the conformational behaviors of azapep-tides in water. During the calculation, we considered the impact of the amide bond in the azapeptide mod-els on the conformational preferences of models 4-6. We analyzed the effect of the hydrogen bond be-tween the side-chain main chain and main-chain main-chain on the conformational behaviors of azapep-tides 4-6. We found that the predicted lowest energy conformation for the three models differs depending on the calculation methods. In the gas phase, B3LYP functional indicates that the conformers tttANP-1 and tttADP-1 of azapeptides 4 and 5 correspond to the type I of -turn, the lowest energy conformation with all-trans amide bonds, respectively. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers tctANP-2 and tctADP-3 of azapeptide 4 and 5, which contain the cis amide bond preceding the Pro residue, as the lowest energy conformation in the gas phase. The results imply that azaAsx and Pro residues may involve cis-trans isomerization in the gas phase. In water, the predict-ed lowest energy conformer of azapeptides 4 and 5 differs from the gas phase results and depends on the calculational method. For azapeptide 6, regardless of calculation methods and phases, tttAAP-1 (-I turn) is predicted as the lowest energy conformer. The results imply that the effect of the side chain that can form hydrogen bonds on the conformational preferences of azapeptides 4 and 5 may not be negligible. We compared the theoretical results of azaXaa-Pro models with those of Pro-azaXaa models, showing that in-corporating azaamino acid residue in peptides at different positions can significantly impact the folding patterns and stability of azapeptides.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Khabchi¹,

Mcharfi²,

Benzakour³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Among peptidomimetics, we focus on azapeptides, a change in the backbone of a peptide by substituting the α-carbon with a nitrogen atom [ 5 , 6 , 7 ]. This modification confers azapeptides more resistance to physiological degradation and long duration of action [ 8 ]. Many studies revealed the importance of incorporating an azaamino acid in the peptide’s sequence to enhance the stability and bioavailability of drug candidates [ 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Many studies revealed the importance of incorporating an azaamino acid in the peptide’s sequence to enhance the stability and bioavailability of drug candidates [ 9 , 10 , 11 , 12 , 13 , 14 ]. In addition, synthetic methods [ 5 , 9 , 11 ] and biological studies [ 5 , 8 , 9 , 12 , 13 , 14 ] of azapeptides have been reported. However, the structural behaviors of azaamino acid residue in peptides remain limited.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

Azapeptides have gained much attention due to their ability to enhance the stability and bioavailability of peptide drugs. Their structural preferences, essential to understanding their function and potential application in the peptide drug design, remain largely unknown. In this work, we systematically investigated the conformational preferences of three azaamino acid residues in tripeptide models, Ac-azaXaa-Pro-NHMe [Xaa = Asn (4), Asp (5), Ala (6)], using the popular DFT functionals, B3LYP and B3LYP-D3. A solvation model density (SMD) was used to mimic the solvation effect on the conformational behaviors of azapeptides in water. During the calculation, we considered the impact of the amide bond in the azapeptide models on the conformational preferences of models 4–6. We analyzed the effect of the HB between the side-chain main chain and main-chain main-chain on the conformational behaviors of azapeptides 4–6. We found that the predicted lowest energy conformation for the three models differs depending on the calculation methods. In the gas phase, B3LYP functional indicates that the conformers tttANP-1 and tttADP-1 of azapeptides 4 and 5 correspond to the type I of β-turn, the lowest energy conformation with all-trans amide bonds. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers tctANP-2 and tctADP-3 of azapeptide 4 and 5, which contain the cis amide bond preceding the Pro residue, as the lowest energy conformation in the gas phase. The results imply that azaAsx and Pro residues may involve cis-trans isomerization in the gas phase. In water, the predicted lowest energy conformer of azapeptides 4 and 5 differs from the gas phase results and depends on the calculational method. For azapeptide 6, regardless of calculation methods and phases, tttAAP-1 (β-I turn) is predicted as the lowest energy conformer. The results imply that the effect of the side chain that can form HBs on the conformational preferences of azapeptides 4 and 5 may not be negligible. We compared the theoretical results of azaXaa-Pro models with those of Pro-azaXaa models, showing that incorporating azaamino acid residue in peptides at different positions can significantly impact the folding patterns and stability of azapeptides.

show abstract

Kinetic study of aza-amino acid incorporation into peptide chains: Influence of the steric effect of the side chain

Cited by 2 publications

References 21 publications

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

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

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

Contact Info

Product

Resources

About