Underestimated Noncovalent Interactions in Protein Data Bank

Noncovalent interactions
(NCIs) play essential roles in the structure
and function of biomacromolecules. There are various NCIs, e.g., hydrogen
bonds (HBs), cation−π and π–π interactions,
and ionic bonds, among which HBs are the most widespread and well-studied.
By utilizing the ratio of the observed HBs over pseudo HBs (1.0 Å
longer than the HB distance criteria without angle constraints), we
demonstrated that HBs in both protein–ligand and protein–protein
interfaces are overlooked in structures deposited in PDB. After the
QM/MM optimization of 12 protein–ligand complexes, we showed
that the overlooked HBs could be recovered. With a systematic search
in the PDB, we found that the HB number per residue (NHB/R) in proteins decreases as structural resolution becomes
lower, implying that HBs are overlooked even today, regardless of
the type of refinement approach used. Similarly, cation−π,
π–π, and ionic interactions were found to be significantly
lost, manifesting the universal underestimation of various NCIs. Considering
the vital role of NCIs, it is important to recover the NCIs to facilitate
drug design, to explore protein–protein interaction, and to
study protein structure and function.