Short Carboxylic Acid-Carboxylate Hydrogen Bonds Can Have Fully Localized Protons

Biochemistry. 2017 Jan 17;56(2):391-402. doi: 10.1021/acs.biochem.6b00906. Epub 2016 Dec 30.

Abstract

Short hydrogen bonds (H-bonds) have been proposed to play key functional roles in several proteins. The location of the proton in short H-bonds is of central importance, as proton delocalization is a defining feature of low-barrier hydrogen bonds (LBHBs). Experimentally determining proton location in H-bonds is challenging. Here, bond length analysis of atomic (1.15-0.98 Å) resolution X-ray crystal structures of the human protein DJ-1 and its bacterial homologue, YajL, was used to determine the protonation states of H-bonded carboxylic acids. DJ-1 contains a buried, dimer-spanning 2.49 Å H-bond between Glu15 and Asp24 that satisfies standard donor-acceptor distance criteria for a LBHB. Bond length analysis indicates that the proton is localized on Asp24, excluding a LBHB at this location. However, similar analysis of the Escherichia coli homologue YajL shows both residues may be protonated at the H-bonded oxygen atoms, potentially consistent with a LBHB. A Protein Data Bank-wide screen identifies candidate carboxylic acid H-bonds in approximately 14% of proteins, which are typically short [⟨dO-O⟩ = 2.542(2) Å]. Chemically similar H-bonds between hydroxylated residues (Ser/Thr/Tyr) and carboxylates show a trend of lengthening O-O distance with increasing H-bond donor pKa. This trend suggests that conventional electronic effects provide an adequate explanation for short, charge-assisted carboxylic acid-carboxylate H-bonds in proteins, without the need to invoke LBHBs in general. This study demonstrates that bond length analysis of atomic resolution X-ray crystal structures provides a useful experimental test of certain candidate LBHBs.

MeSH terms

  • Aspartic Acid / chemistry*
  • Aspartic Acid / metabolism
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / metabolism
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism
  • Gene Expression
  • Glutamic Acid / chemistry*
  • Glutamic Acid / metabolism
  • Humans
  • Hydrogen Bonding
  • Hydroxylation
  • Models, Molecular
  • Protein Deglycase DJ-1 / chemistry*
  • Protein Deglycase DJ-1 / genetics
  • Protein Deglycase DJ-1 / metabolism
  • Protein Domains
  • Protein Processing, Post-Translational*
  • Protein Structure, Secondary
  • Protons*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribosomal Proteins / chemistry*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism

Substances

  • Carboxylic Acids
  • Escherichia coli Proteins
  • Protons
  • Recombinant Proteins
  • Ribosomal Proteins
  • YajL protein, E coli
  • Aspartic Acid
  • Glutamic Acid
  • PARK7 protein, human
  • Protein Deglycase DJ-1