Imidazole Nitrogens of Two Histidine Residues Participating in N–H···N Hydrogen Bonds in Protein Structures: Structural Bioinformatics Approach Combined with Quantum Chemical Calculations

Abstract

Protein structures are stabilized by different types of hydrogen bonds. However, unlike the DNA double helical structure, the N-H···N type of hydrogen bonds is relatively rare in proteins. N-H···N hydrogen bonds formed by imidazole groups of two histidine residues have not been investigated. We have systematically analyzed 5333 high-resolution protein structures with resolution 1.8 Å or better and identified 285 histidine pairs in which the nitrogen atoms of the imidazole side chains can potentially participate in N-H···N hydrogen bonds. The histidine pairs were further divided into two groups, neutral-neutral and protonated-neutral, depending on the protonation state of the donor histidine. Quantum chemical calculations were performed on imidazole groups adopting the same geometry observed in the protein structures. Average interaction energies between the interacting imidazole groups are -6.45 and -22.5 kcal/mol for neutral-neutral and protonated-neutral, respectively. Hydrogen bond interaction between the imidazole moieties is further confirmed by natural bond orbital analyses of the model compounds. Histidine residues involved in N-H···N hydrogen bonds are relatively more buried and have low B-factor values in the protein structures. N-H···N hydrogen bond formed by a pair of buried histidine residues can significantly contribute to the structural stability of proteins.

Structural Differences In 3C-like protease (Mpro) From SARS-CoV and SARS-CoV-2: Molecular Insights For Drug Repurposing Against COVID-19 Revealed by Molecular Dynamics Simulations

“…However, a new network of H-bond was formed in case of SARS-CoV-2: H41 with H164, which is also one of the residues involved in active site formation. Such N-H···N hydrogen bonds formed by imidazole groups of two histidine residues (H41: H164) are rare in proteins [35]. Our SASA analysis indicated that H41 & H164 are relatively buried and such N-H···N H-bonds formed by a pair of buried histidine, may significantly contribute to structural stability [35] of the SARS-CoV-2 Mpro which is evident by our above RMSD and RMSF analysis.…”

“…Such N-H···N hydrogen bonds formed by imidazole groups of two histidine residues (H41: H164) are rare in proteins [35]. Our SASA analysis indicated that H41 & H164 are relatively buried and such N-H···N H-bonds formed by a pair of buried histidine, may significantly contribute to structural stability [35] of the SARS-CoV-2 Mpro which is evident by our above RMSD and RMSF analysis. There is no change in the network of C145 catalytic residues which indicates that the integrity of C145 may be very essential for its conserved protease activity.…”

When Are Two Hydrogen Bonds Better than One? Accurate First-Principles Models Explain the Balance of Hydrogen Bond Donors and Acceptors Found in Proteins

“…Among these, hydrogen bonds (HBs) are a particularly critical class of noncovalent interactions for biological function. The definition of the HB has become more encompassing over the years 20 , expanding to include a range of interactions such as N-H•••N [21][22][23][24] , sulfur-containing [25][26][27] , X-H π [28][29] , and C-H•••O [30][31][32][33][34] , among others. Nevertheless, the HB is generally distinguished from other noncovalent interactions by its fairly strong electrostatic component 35 with evidence of some covalent [36][37][38] bond formation 20,39 , as supported by the interaction being directional in nature 40 .…”

When Are Two Hydrogen Bonds Better than One? Accurate First-Principles Models Explain the Balance of Hydrogen Bond Donors and Acceptors Found in Proteins

“…Among these, hydrogen bonds (HBs) are a particularly critical class of noncovalent interactions for biological function. The definition of the HB has become more encompassing over the years 20 , expanding to include a range of interactions such as N-H•••N [21][22][23][24] , sulfur-containing [25][26][27] , X-H π [28][29] , and C-H•••O [30][31][32][33][34] , among others. Nevertheless, the HB is generally distinguished from other noncovalent interactions by its fairly strong electrostatic component 35 with evidence of some covalent [36][37][38] bond formation 20,39 , as supported by the interaction being directional in nature 40 .…”