I'm studying a protein containing heme. Can Glide handle the metal coordination if the ligand is not anionic?

The GlideScore includes a special metal reward term that is activated only for the binding of anionic ligands to net-positive metal centers, allowing Glide to recognize the observed strong preference for such interactions in metalloproteases. For example, the imidazole-metal interaction would not be eligible for this reward. In Suite 2011, this reward was extended to increase the reward for bidentate ligands in which one atom is polar but neutral and the other is anionic. However, even if your ligand-metal interaction does not qualify for this special reward term, the Coulomb/vdW interactions are included in the GlideScore and should favor metal binding. If you find that Glide is having trouble positioning the ligand correctly, you could apply a metal constraint (which must be defined during Grid Generation).

Also, if a hydrogen is displaced from the ligand when the ligand binds to the metal, you can use Epik to generate extra deprotonated states for metal binding, even though these states do not normally have appreciable concentrations at physiological pH.

Keywords: ligand-metal interaction, metal binding, anionic ligands, Glide, Epik

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