Considerations for Generating FEP Maps

When choosing a protein and a set of ligands for binding energy estimations with FEP+, you should consider the following:

Binding mode—only series with the same putative binding mode should be grouped for one map.

Charge—perturbations between ligands with different net charges may need an increased amount of simulation to converge the results.

Protein conformations—only ligands with similar protein conformation for the holo complexes should be grouped.  If the holo complexes of some of the ligands have very different conformations, you should separate them into different groups and run FEP+ separately for each group.

Waters—crystal waters are recommended to be retained unless they have severe steric clashes with the ligands modeled.

Protein structure—if multiple crystal structures are available, select the crystal structure with the highest resolution, and with the crystal ligand that is most similar to the compounds to be modeled in FEP+ jobs.

Structure Preparation—run the Protein Preparation Wizard on the protein.  Run LigPrep with Epik to make sure the ligands are also appropriately prepared. Check the protonation and tautomeric states of the ligands to ensure they complement the protein environment.

Alignment—run core-constrained Glide docking to dock the ligands to the receptor and align the core to the crystal ligand.

Also, see Requirements on Experimental Structures and Binding Affinity Data for FEP+.