Accurate computation of protein-ligand binding free energy remains an elusive goal due to inherent difficulties involved in the accurate calculation of gas-phase protein-ligand interaction energy, the entropy, and the solvation energy. In this study, we explore the use of fragment quantum chemical calculations for improved accuracy in protein-ligand binding free energy calculations. The present work demonstrated that the gas-phase protein-ligand interaction energies can be accurately calculated by the molecular fractionation with conjugate caps method as verified by comparison with the full quantum calculations for several protein-ligand systems. The m06-2