Tomita Naoki, Onoda Hiroki, Chavas Leonard M G, Chikenji George
Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Nagoya University Synchrotron Radiation Research Center, Nagoya University, Nagoya, Aichi 464-8603, Japan.
Biophys Physicobiol. 2025 Feb 1;22(1):e220005. doi: 10.2142/biophysico.bppb-v22.0005. eCollection 2025.
Proteins typically fold into unique three-dimensional structures largely driven by interactions between hydrophobic amino acids. This understanding has helped improve our knowledge of protein folding. However, recent research has shown an exception to this idea, demonstrating that specific threonine-rich peptides have a strong tendency to form β-hairpin structures, even in the highly hydrophilic amino acid sequences. This finding suggests that the hydrophilic amino acid sequence space still leaves room for exploring foldable amino acid sequences. In this study, we conducted a systematic exploration of the repetitive amino acid sequence space by AlphaFold2 (AF2), with a focus on sequences composed exclusively of hydrophilic residues, to investigate their potential for adopting unique structures. As a result, the sequence space exploration suggested that several repetitive threonine-rich sequences adopt distinctive conformations and these conformational shapes can be influenced by the length of the sequence unit. Moreover, the analysis of structural dataset suggested that threonine contributes to the structural stabilization by forming non-polar atom packing that tolerates unsatisfied hydrogen bonds, and while also supporting other residues in forming hydrogen bonds. Our findings will broaden the horizons for the discovery of foldable amino acid sequences consisting solely of hydrophilic residues and help us clarify the unknown mechanisms of protein structural stabilization.
蛋白质通常折叠成独特的三维结构，这在很大程度上是由疏水氨基酸之间的相互作用驱动的。这种认识有助于增进我们对蛋白质折叠的了解。然而，最近的研究表明了这一观点存在例外情况，证明特定的富含苏氨酸的肽即使在高度亲水的氨基酸序列中也有强烈形成β-发夹结构的倾向。这一发现表明，亲水氨基酸序列空间仍为探索可折叠氨基酸序列留有空间。在本研究中，我们利用AlphaFold2（AF2）对重复氨基酸序列空间进行了系统探索，重点关注完全由亲水残基组成的序列，以研究它们形成独特结构的潜力。结果，序列空间探索表明，几个富含苏氨酸的重复序列呈现出独特的构象，并且这些构象形状会受到序列单元长度的影响。此外，对结构数据集的分析表明，苏氨酸通过形成容忍未满足氢键的非极性原子堆积来促进结构稳定，同时也支持其他残基形成氢键。我们的发现将拓宽仅由亲水残基组成的可折叠氨基酸序列的发现视野，并帮助我们阐明蛋白质结构稳定的未知机制。
