LIMAS, Department of Chemistry, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdallah University, Fez 30000, Morocco.
Department of Chemistry Education, Daegu University, Daegudae-ro 201, Gyeongsan-si 38453, Republic of Korea.
Molecules. 2023 Jul 17;28(14):5454. doi: 10.3390/molecules28145454.
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 (), Asp (), Ala ()], 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 -. We analyzed the effect of the HB between the side-chain main chain and main-chain main-chain on the conformational behaviors of azapeptides -. 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 and of azapeptides and correspond to the type I of β-turn, the lowest energy conformation with all- amide bonds. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers and of azapeptide and , which contain the 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 - isomerization in the gas phase. In water, the predicted lowest energy conformer of azapeptides and differs from the gas phase results and depends on the calculational method. For azapeptide , regardless of calculation methods and phases, (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 and 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.
氮杂肽因其能够提高肽类药物的稳定性和生物利用度而备受关注。它们的结构偏好对于理解其功能和在肽类药物设计中的潜在应用至关重要，但这些结构偏好在很大程度上仍然未知。在这项工作中，我们使用流行的 DFT 泛函 B3LYP 和 B3LYP-D3，系统地研究了三肽模型中三种氮杂氨基酸残基（Ac-azaXaa-Pro-NHMe [Xaa = Asn ()、Asp ()、Ala ()]）的构象偏好。使用溶剂化模型密度 (SMD) 模拟水对氮杂肽构象行为的溶剂化效应。在计算过程中，我们考虑了酰胺键在氮杂肽模型中对模型构象偏好的影响。我们分析了侧链主链和主链主链之间氢键 (HB) 对氮杂肽构象行为的影响。我们发现，三种模型的预测最低能量构象取决于计算方法的不同。在气相中，B3LYP 泛函表明氮杂肽和的构象和对应于 I 型β-转角，这是所有酰胺键的最低能量构象。考虑到色散校正，B3LYP-D3 泛函预测氮杂肽和中包含 Pro 残基前的酰胺键的构象和，它们是气相中的最低能量构象。结果表明，氮杂 Asx 和 Pro 残基在气相中可能涉及到 - 异构化。在水中，氮杂肽和的预测最低能量构象与气相结果不同，并且取决于计算方法。对于氮杂肽，无论计算方法和相如何，（β-I 转角）都被预测为最低能量构象。结果表明，侧链形成氢键的能力对氮杂肽和构象偏好的影响可能不可忽略。我们将氮杂 Xaa-Pro 模型的理论结果与 Pro-azaXaa 模型的理论结果进行了比较，结果表明，在肽中不同位置掺入氮杂氨基酸残基会显著影响氮杂肽的折叠模式和稳定性。
