free energy perturbation with schrödinger fep/rest
Schrödinger 16.4 FEP+
OPLS3 force field
Windows per transformation: 12
Assumed pH 7.4
Typical simulation time per window: 5 ns
Default parameters as described in Wang et al. 2015 JACS
For prediction set 2, the protein structure 1kjyp chain A was used for all simulations. The protein was prepared using the Protein Preparation Wizard in Maestro. Protonation states were assigned assuming a pH of 7.4. Crystal waters close within 4 A of the X-ray ligand were retained for the calculations. The ligands were represented by the OPLS3 force field. Torsional parameters that were not available were generated using the Force Field Builder in Maestro. Ligand conformations were generated from the smiles strings using corina. Ligands were aligned to the X-ray ligand using the Flexible Ligand Alignment tool in Maestro and the resulting binding mode was inspected visually. If applicable, both binding modes resulting from alignment with two states found in Xray were considered. The systems were solvated in a water box with a buffer width of 5 A for complex simulations and 10 A for solvent simulations. The systems were relaxed and equilibrated using the default Desmond relaxation protocol.A total of 12 lambda windows were simulated for each FEP/Rest calculations using a simulation time of 5ns per window and NPT ensemble conditions. Replica exchanges between neighboring windows were attempted every 1.2 ps. The Bennett Acceptance Ratio method was used to calculate the free energy and errors for the predictions were estimated using the cycle closure algorithm. Simulations that displayed high errors were removed from the final FEP map (indicated by red color in Maestro FEP Mapper Analysis window). In cases of multiple binding modes, the better scoring binding mode was used to calculate the final relative free energy.
Maestro/Corina maunal alignment method
Schrödinger Maestro/Corina
Assumed pH 7.4
Tautomers considered
Gasteiger charges
Ligand conformations were generated from the smiles strings using corina with driver options dh,canon.
Alignment based on maximum common core (Canvas).
Ligands were aligned to the X-ray ligand using the Flexible Ligand Alignment tool in Maestro and the resulting binding mode was inspected visually. Both possible binding modes from the Xray were considered as binding modes for FEP calculations.