Hydrogen bonds (HBs) play an essential role in the structure and catalytic action of enzymes, but a complete understanding of HBs in proteins challenges the resolution of modern structural (i.e., X-ray diffraction) techniques and mandates computationally demanding electronic structure methods from correlated wavefunction theory for predictive accuracy. Numerous amino acid sidechains contain functional groups (e.g., hydroxyls in Ser/Thr or Tyr and amides in Asn/Gln) that can act as either HB acceptors or donors (HBA/HBD) and even form simultaneous, ambifunctional HB interactions. To understand the relative energetic benefit of each interaction, we characterize the potential energy surfaces of representative model systems with accurate coupled cluster theory calculations. To reveal the relationship of these energetics to the balance of these interactions in proteins, we curate a set of 4000 HBs, of which >500 are ambifunctional HBs, in high-resolution protein structures. We show that our model systems accurately predict the favored HB structural properties. Differences are apparent in HBA/HBD preference for aromatic Tyr versus aliphatic Ser/Thr hydroxyls because Tyr forms significantly stronger O–H⋯O HBs than N–H⋯O HBs in contrast to comparable strengths of the two for Ser/Thr. Despite this residue-specific distinction, all models of residue pairs indicate an energetic benefit for simultaneous HBA and HBD interactions in an ambifunctional HB. Although the stabilization is less than the additive maximum due both to geometric constraints and many-body electronic effects, a wide range of ambifunctional HB geometries are more favorable than any single HB interaction.

中文翻译：

---

什么时候两个氢键比一个更好？准确的第一性原理模型解释了蛋白质中氢键供体和受体的平衡

氢键 (HBs) 在酶的结构和催化作用中起着至关重要的作用，但对蛋白质中 HBs 的全面了解对现代结构（即X 射线衍射）技术的分辨率提出了挑战，并要求从相关的计算要求的电子结构方法用于预测准确性的波函数理论。许多氨基酸侧链含有官能团（例如, Ser/Thr 或 Tyr 中的羟基和 Asn/Gln 中的酰胺) 可以作为 HB 受体或供体 (HBA/HBD) 甚至形成同时的双功能 HB 相互作用。为了了解每种相互作用的相对能量益处，我们用精确的耦合集群理论计算来描述代表性模型系统的势能面。为了揭示这些能量学与蛋白质中这些相互作用的平衡之间的关系，我们在高分辨率蛋白质结构中策划了一组 4000 个 HBs，其中 >500 个是双功能 HBs。我们表明，我们的模型系统准确地预测了有利的 HB 结构特性。HBA/HBD 偏好芳香族 Tyr与脂肪族 Ser/Thr 羟基，因为 Tyr 形成的 O-H⋯O HBs 比 N-H⋯O HBs 显着更强，而两者的 Ser/Thr 强度相当。尽管存在这种特定于残基的区别，但所有残基对模型都表明在双功能 HB 中同时 HBA 和 HBD 相互作用具有能量优势。尽管由于几何约束和多体电子效应，稳定性小于加性最大值，但广泛的双功能 HB 几何形状比任何单个 HB 相互作用更有利。