Improving the accuracy of predicting protein-ligand binding-free energy with semiempirical quantum chemistry charge

Aim: It is a challenge to predict binding-free energy (ΔG) accurately. Methodology/results: For accurate ΔG prediction, a new strategy combining solvated interaction energy (SIE) or molecular mechanics/generalized Born surface area (MM/GBSA) approach with the Coulson charge of both protein and ligand calculated by semiempirical quantum mechanics (SQM), named SIE-SQMPC or MM/GBSA-SQMPC approach, was developed and tested on 50 protein-ligand complexes. Both approaches achieved higher correlation (R²) between experimental and predicted ΔG than that with Amber-ff03 charge, even for ligands with highly different scaffolds. But, SIE-SQMPC is computationally much faster than MM/GBSA-SQMPC. Conclusion: SIE-SQMPC provided an effective alternative to predict ΔG of protein-ligand binding (R² = 0.66-0.94 for SIE-AM1; R² = 0.59-0.98 for SIE-PM7), which has the potential of high-throughput processing for molecular docking and drug design.