El Khabchi, M.; Mcharfi, M.; Benzakour, M.; Fitri, A.; Benjelloun, A.T.; Song, J.-W.; Lee, K.-B.; Lee, H.-J. Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis. Molecules2023, 28, 5454.
El Khabchi, M.; Mcharfi, M.; Benzakour, M.; Fitri, A.; Benjelloun, A.T.; Song, J.-W.; Lee, K.-B.; Lee, H.-J. Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis. Molecules 2023, 28, 5454.
El Khabchi, M.; Mcharfi, M.; Benzakour, M.; Fitri, A.; Benjelloun, A.T.; Song, J.-W.; Lee, K.-B.; Lee, H.-J. Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis. Molecules2023, 28, 5454.
El Khabchi, M.; Mcharfi, M.; Benzakour, M.; Fitri, A.; Benjelloun, A.T.; Song, J.-W.; Lee, K.-B.; Lee, H.-J. Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis. Molecules 2023, 28, 5454.
Abstract
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.
Chemistry and Materials Science, Theoretical Chemistry
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