Effect of Differential Geminal Substitution of γ Amino Acid Residues at the (i + 2) Position of αγ Turn Segments on the Conformation of Template β-Hairpin Peptides,The Journal of Organic Chemistry

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Effect of Differential Geminal Substitution of γ Amino Acid Residues at the (i + 2) Position of αγ Turn Segments on the Conformation of Template β-Hairpin Peptides
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2021-08-16 , DOI: 10.1021/acs.joc.1c00351
Swapna Debnath ₁ , Suvankar Ghosh ₂ , Gopal Pandit ₁ , Priyadarshi Satpati ₂ , Sunanda Chatterjee ₁

Affiliation

The effect of insertion of three geminally dimethyl substituted γ amino acid residues [γ^2,2 (4-amino-2,2-dimethylbutanoic acid), γ^3,3 (4-amino-3,3-dimethylbutanoic acid), and γ^4,4 (4-amino-4,4-dimethylbutanoic acid)] at the (i + 2) position of a two-residue αγ C₁₂ turn segment in a model octapeptide sequence Leu-Phe-Val-Aib-Xxx-Leu-Phe-Val (where Xxx = γ amino acid residues) has been investigated in this study. Solution conformational studies (NMR, CD, and IR) and ab initio calculations indicated that γ^3,3 and γ^4,4 residues were well accommodated in the β-hairpin nucleating αγ C₁₂ turns, which gave rise to well-registered hairpins, in contrast to γ^2,2, which was unable to form a tight C₁₂ β-hairpin nucleating turn and promote a well-registered β-hairpin. Geminal disubstitution at the C^α carbon in γ^2,2 led to unfavorable steric contacts, disabling its accommodation in the αγ C₁₂ hairpin nucleating turn unlike the γ^3,3 and γ^4,4 residues. Geminal substitutions at different carbons along the backbone constrained backbone torsion angles for the three γ amino acid residues differently, generating diverse conformational preferences in them. Folded hairpins were energetically more stable (∼8 to 9 kcal/mol) than the unfolded peptides. Conformational preference of the peptides was independent of the N-terminal protecting group. Such fundamental understanding will instrumentalize the future directed design of foldamers.

中文翻译：

在αγ转角片段的（i + 2）位置γ氨基酸残基的差异双生取代对模板β-发夹肽构象的影响

插入三个双二甲基取代的 γ 氨基酸残基 [γ ^2,2 (4-氨基-2,2-二甲基丁酸)、γ ^3,3 (4-氨基-3,3-二甲基丁酸) 和 γ 的影响^4,4 (4-氨基-4,4-二甲基丁酸)] 在模型八肽序列 Leu-Phe-Val-Aib-Xxx-Leu中的两个残基 αγ C ₁₂转角区段的 ( i + 2) 位置-Phe-Val（其中 Xxx = γ 氨基酸残基）已在本研究中进行了研究。溶液构象研究（NMR、CD 和 IR）和从头计算表明 γ ^3,3和 γ ^4,4残基很好地容纳在 β-发夹成核 αγ C _{12 中}与γ ^2,2形成鲜明对比的是，γ ^2,2不能形成紧密的C ₁₂ β-发夹成核转角并促进良好记录的β-发夹。与γ ^3,3和γ ^4,4不同，γ ^{2,2 中}C ^α碳处的成对置换导致不利的空间接触，使其无法适应αγ C ₁₂发夹形核转角残留物。沿主链的不同碳原子处的双生替换以不同方式限制了三个 γ 氨基酸残基的主链扭转角，从而在其中产生了不同的构象偏好。折叠的发夹在能量上比未折叠的肽更稳定（~8 到 9 kcal/mol）。肽的构象偏好不依赖于 N 端保护基团。这种基本的理解将有助于未来的折叠器定向设计。

更新日期：2021-09-03

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