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Hydrogen bonds (HB)s are the most abundant motifs in biological systems. They play a key role in determining protein–ligand binding affinity and selectivity. We designed two pharmaceutically beneficial HB databases, database A including ca. 12,000 protein–ligand complexes with ca. 22,000 HBs and their geometries, and database B including ca. 400 protein–ligand complexes with ca. 2200 HBs, their geometries, and bond strengths determined via our local vibrational mode analysis. We identified seven major HB patterns, which can be utilized as a de novo QSAR model to predict the binding affinity for a specific protein–ligand complex. Glycine was reported as the most abundant amino acid residue in both donor and acceptor profiles, and N–H⋯O was the most frequent HB type found in database A. HBs were preferred to be in the linear range, and linear HBs were identified as the strongest. HBs with HB angles in the range of 100–110°, typically forming intramolecular five-membered ring structures, showed good hydrophobic properties and membrane permeability. Utilizing database B, we found a generalized Badger’s relationship for more than 2200 protein–ligand HBs. In addition, the strength and occurrence maps between each amino acid residue and ligand functional groups open an attractive possibility for a novel drug-design approach and for determining drug selectivity and affinity, and they can also serve as an important tool for the hit-to-lead process.
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When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins
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.
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- Award ID(s):
- 1704266
- PAR ID:
- 10287724
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 12
- Issue:
- 3
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 1147 to 1162
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D0SC05084A
