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
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
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DOI：
10.1021/acs.joc.1c00351
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发表时间：
2021-08-16
影响因子：
3.6
通讯作者：
Chatterjee, Sunanda
中科院分区：
文献类型：
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作者：
Debnath, Swapna;Ghosh, Suvankar;Chatterjee, Sunanda
本文研究了在模型八肽序列Leu-Phe-Val-AIB-xxx-Leu-Phe-Val(其中xxx=氨基酸残基)的两个残基的(i+2)位插入三个二甲基取代的伽马氨基酸残基[Gamma(2，2)(4-氨基-2，2-二甲基丁酸)、Gamma(3，3)(4-氨基-3，3-二甲基丁酸)和Gamma(4，4)(4-氨基-4，4-二甲基丁酸)]的影响。溶液构象研究(核磁共振、CD和IR)和从头计算表明，伽马(3，3)和伽马(4，4)残基在β-发夹形核α-C-12转角中被很好地容纳，从而产生了良好的发夹，而伽马(2，2)则无法形成紧密的C-12β-发夹成核转角，促进了注册良好的β-发夹。与伽马(3，3)和伽马(4，4)残基不同，Gemina在伽马(2，2)中C-α碳的二取代导致了不利的空间接触，使其无法适应α-伽马C-12发夹成核转折。骨架上不同碳原子上的Gemina取代以不同的方式限制了三个伽马氨基酸残基的骨架扭转角，从而产生了不同的构象偏好。折叠的发夹比未折叠的多肽在能量上更稳定(类似于8-9千卡/摩尔)。多肽的构象选择性不受N-端保护基团的影响。这种基本的理解将有助于未来对折叠器的定向设计。
The effect of insertion of three geminally dimethyl substituted gamma amino acid residues [gamma(2,2) (4-amino-2,2-dimethylbutanoic acid), gamma(3,3) (4-amino-3,3-dimethylbutanoic acid), and gamma(4,4) (4-amino-4,4-dimethylbutanoic acid)] at the (i + 2) position of a two-residue alpha gamma C-12 turn segment in a model octapeptide sequence Leu-Phe-Val-Aib-Xxx-Leu-Phe-Val (where Xxx = gamma amino acid residues) has been investigated in this study. Solution conformational studies (NMR, CD, and IR) and ab initio calculations indicated that gamma(3,3) and gamma(4,4) residues were well accommodated in the beta-hairpin nucleating alpha gamma C-12 turns, which gave rise to well-registered hairpins, in contrast to gamma(2,2), which was unable to form a tight C-12 beta-hairpin nucleating turn and promote a well-registered beta-hairpin. Geminal disubstitution at the C-alpha carbon in gamma(2,2) led to unfavorable steric contacts, disabling its accommodation in the alpha gamma C-12 hairpin nucleating turn unlike the gamma(3,3) and gamma(4,4) residues. Geminal substitutions at different carbons along the backbone constrained backbone torsion angles for the three gamma amino acid residues differently, generating diverse conformational preferences in them. Folded hairpins were energetically more stable (similar to 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.