  Many biologically important ligands of proteins are large, flexible, and
often charged molecules that bind to extended regions on the protein surface.
It is infeasible or expensive to locate such ligands on proteins with standard
methods such as docking or molecular dynamics (MD) simulation. The alternative
approach proposed here is the scanning of a spatial and angular grid around the
protein with smaller fragments of the large ligand. Energy values for complete
grids can be computed efficiently with a well-known Fast Fourier Transform
accelerated algorithm and a physically meaningful interaction model. We show
that the approach can readily incorporate flexibility of protein and ligand.
The energy grids (EGs) resulting from the ligand fragment scans can be
transformed into probability distributions, and then directly compared to
probability distributions estimated from MD simulations and experimental
structural data. We test the approach on a diverse set of complexes between
proteins and large, flexible ligands, including a complex of Sonic Hedgehog
protein and heparin, three heparin sulfate substrates or non-substrates of an
epimerase, a multi-branched supramolecular ligand that stabilizes a
protein-peptide complex, and a flexible zwitterionic ligand that binds to a
surface basin of a Kringle domain. In all cases the EG approach gives results
that are in good agreement with experimental data or MD simulations.
