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

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 systematic...

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Autores principales: El Khabchi, Mouna, Mcharfi, Mohammed, Benzakour, Mohammed, Fitri, Asmae, Benjelloun, Adil Touimi, Song, Jong-Won, Lee, Kang-Bong, Lee, Ho-Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386235/
https://www.ncbi.nlm.nih.gov/pubmed/37513326
http://dx.doi.org/10.3390/molecules28145454
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author El Khabchi, Mouna
Mcharfi, Mohammed
Benzakour, Mohammed
Fitri, Asmae
Benjelloun, Adil Touimi
Song, Jong-Won
Lee, Kang-Bong
Lee, Ho-Jin
author_facet El Khabchi, Mouna
Mcharfi, Mohammed
Benzakour, Mohammed
Fitri, Asmae
Benjelloun, Adil Touimi
Song, Jong-Won
Lee, Kang-Bong
Lee, Ho-Jin
author_sort El Khabchi, Mouna
collection PubMed
description 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.
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spelling pubmed-103862352023-07-30 Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis El Khabchi, Mouna Mcharfi, Mohammed Benzakour, Mohammed Fitri, Asmae Benjelloun, Adil Touimi Song, Jong-Won Lee, Kang-Bong Lee, Ho-Jin Molecules Article 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. MDPI 2023-07-17 /pmc/articles/PMC10386235/ /pubmed/37513326 http://dx.doi.org/10.3390/molecules28145454 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
El Khabchi, Mouna
Mcharfi, Mohammed
Benzakour, Mohammed
Fitri, Asmae
Benjelloun, Adil Touimi
Song, Jong-Won
Lee, Kang-Bong
Lee, Ho-Jin
Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title_full Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title_fullStr Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title_full_unstemmed Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title_short Computational Investigation of Conformational Properties of Short Azapeptides: Insights from DFT Study and NBO Analysis
title_sort computational investigation of conformational properties of short azapeptides: insights from dft study and nbo analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10386235/
https://www.ncbi.nlm.nih.gov/pubmed/37513326
http://dx.doi.org/10.3390/molecules28145454
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