Large-Scale Analysis of Hydrogen Bond Interaction Patterns in Protein–Ligand Interfaces

Protein–ligand
interactions are the fundamental basis for
molecular design in pharmaceutical research, biocatalysis, and agrochemical
development. Especially hydrogen bonds are known to have special geometric
requirements and therefore deserve a detailed analysis. In modeling
approaches a more general description of hydrogen bond geometries,
using distance and directionality, is applied. A first study of their
geometries was performed based on 15 protein structures in 1982. Currently
there are about 95 000 protein–ligand structures available
in the PDB, providing a solid foundation for a new large-scale statistical
analysis. Here, we report a comprehensive investigation of geometric
and functional properties of hydrogen bonds. Out of 22 defined functional
groups, eight are fully in accordance with theoretical predictions
while 14 show variations from expected values. On the basis of these
results, we derived interaction geometries to improve current computational
models. It is expected that these observations will be useful in designing
new chemical structures for biological applications.