Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
J Phys Chem B. 2024 Sep 12;128(36):8687-8700. doi: 10.1021/acs.jpcb.4c04774. Epub 2024 Sep 2.
Aromatic residues can participate in various biomolecular interactions, such as π-π, cation-π, and CH-π interactions, which are essential for protein structure and function. Here, we re-evaluate the geometry and energetics of these interactions using quantum mechanical (QM) calculations, focusing on pairwise interactions involving the aromatic amino acids Phe, Tyr, and Trp and the cationic amino acids Arg and Lys. Our findings reveal that π-π interactions, while energetically favorable, are less abundant in structured proteins than commonly assumed and are often overshadowed by previously underappreciated, yet prevalent, CH-π interactions. Cation-π interactions, particularly those involving Arg, show strong binding energies and a specific geometric preference toward stacked conformations, despite the global QM minimum, suggesting that a rather perpendicular T-shape conformation should be more favorable. Our results support a more nuanced understanding of protein stabilization via interactions involving aromatic residues. On the one hand, our results challenge the traditional emphasis on π-π interactions in structured proteins by showing that CH-π and cation-π interactions contribute significantly to their structure. On the other hand, π-π interactions appear to be key stabilizers in solvated regions and thus may be particularly important to the stabilization of intrinsically disordered proteins.
芳香族残基可以参与各种生物分子相互作用，如π-π、阳离子-π 和 CH-π 相互作用，这些相互作用对蛋白质的结构和功能至关重要。在这里，我们使用量子力学 (QM) 计算重新评估这些相互作用的几何形状和能量学，重点关注涉及芳香族氨基酸 Phe、Tyr 和 Trp 以及阳离子氨基酸 Arg 和 Lys 的成对相互作用。我们的研究结果表明，虽然 π-π 相互作用在能量上是有利的，但在结构蛋白中并不像通常假设的那样丰富，而且往往被以前被低估但普遍存在的 CH-π 相互作用所掩盖。阳离子-π 相互作用，特别是涉及 Arg 的相互作用，表现出很强的结合能和对堆叠构象的特定几何偏好，尽管存在全局 QM 最小值，这表明相当垂直的 T 形构象应该更有利。我们的结果支持了通过涉及芳香族残基的相互作用更细致地理解蛋白质稳定性的观点。一方面，我们的结果通过表明 CH-π 和阳离子-π 相互作用对它们的结构有重要贡献，挑战了结构蛋白中对 π-π 相互作用的传统强调。另一方面，π-π 相互作用似乎是溶剂化区域的关键稳定剂，因此可能对无规卷曲蛋白质的稳定特别重要。
