Alchemical FEP Calculations of Ligand Conformer Focusing in Explicit Solvent

Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of “focusing” on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5–10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions.