A Distributional Model of Bound Ligand Conformational Strain: From Small Molecules up to Large Peptidic Macrocycles

The internal conformational strain incurred by ligands upon binding
a target site has a critical impact on binding affinity, and expectations
about the magnitude of ligand strain guide conformational search protocols.
Estimates for bound ligand strain begin with modeled ligand atomic
coordinates from X-ray co-crystal structures. By deriving low-energy
conformational ensembles to fit X-ray diffraction data, calculated
strain energies are substantially reduced compared with prior approaches.
We show that the distribution of expected global strain energy values
is dependent on molecular size in a superlinear manner. The distribution
of strain energy follows a rectified normal distribution whose mean
and variance are related to conformational complexity. The modeled
strain distribution closely matches calculated strain values from
experimental data comprising over 3000 protein–ligand complexes.
The distributional model has direct implications for conformational
search protocols as well as for directions in molecular design.