Peripheral cyclic β-amino acids balance the stability and edge-protection of β-sandwiches†,Organic & Biomolecular Chemistry

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Peripheral cyclic β-amino acids balance the stability and edge-protection of β-sandwiches†
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2018-07-16 00:00:00 , DOI: 10.1039/c8ob01322e
Gábor Olajos _{1,

2,

3,

4,

5} , Anasztázia Hetényi _{3,

4,

5,

6} , Edit Wéber _{1,

2,

3,

4,

5} , Titanilla Szögi _{3,

4,

5,

6} , Lívia Fülöp _{3,

4,

5,

6} , Tamás A. Martinek _{1,

2,

3,

4,

5}

Affiliation

Engineering water-soluble stand-alone β-sandwich mimetics is a current challenge because of the difficulties associated with tailoring long-range interactions. In this work, single cis-(1R,2S)-2-aminocyclohexanecarboxylic acid mutations were introduced into the edge strands of the eight-stranded β-sandwich mimetic structures from the betabellin family. Temperature-dependent NMR and CD measurements, together with thermodynamic analyses, demonstrated that the modified peripheral strands exhibited an irregular and partially disordered structure but were able to exert sufficient shielding on the hydrophobic core to retain the predominantly β-sandwich structure. Although the frustrated interactions decreased the free energy of unfolding, the temperature of the maximum stabilities increased to or remained at physiologically relevant temperatures. We found that the irregular peripheral strands were able to prevent edge-to-edge association and fibril formation in the aggregation-prone model. These findings establish a β-sandwich stabilization and aggregation inhibition approach, which does not interfere with the pillars of the peptide bond or change the net charge of the peptide.

中文翻译：

外围环状β-氨基酸平衡了β-三明治的稳定性和边缘保护作用†

工程化水溶性独立的β-三明治模拟物是当前的挑战，因为与定制远距离相互作用相关的困难。在这项工作中，单顺式-（1 R，2 S）-2-氨基环己烷羧酸突变被引入到贝贝林家族的八链β-三明治模拟结构的边缘链中。温度相关的NMR和CD测量以及热力学分析表明，修饰的外围链显示出不规则且部分无序的结构，但能够对疏水核施加足够的屏蔽作用以保留主要的β-三明治结构。尽管沮丧的相互作用降低了展开的自由能，但是最大稳定性的温度增加到或保持在生理上相关的温度。我们发现不规则的外围链能够防止边缘到边缘的关联和易于聚集模型中的原纤维形成。

更新日期：2018-07-16

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