Molecular Binding Sites Are Located Near the Interface of Intrinsic Dynamics Domains (IDDs)

We provide evidence supporting that
protein–protein and
protein–ligand docking poses are functions of protein shape
and intrinsic dynamics. Over sets of 68 protein–protein complexes
and 240 nonhomologous enzymes, we recognize common predispositions
for binding sites to have minimal vibrations and angular momenta,
while two interacting proteins orient so as to maximize the angle
between their rotation/bending axes (>65°). The findings are
then used to define quantitative criteria to filter out docking decoys
less likely to be the near-native poses; hence, the chances to find
near-native hits can be doubled. With the novel approach to partition
a protein into “domains” of robust but disparate intrinsic
dynamics, 90% of catalytic residues in enzymes can be found within
the first 50% of the residues closest to the interface of these dynamics
domains. The results suggest an anisotropic rather than isotropic
distribution of catalytic residues near the mass centers of enzymes.