The present invention provides for the first time a quantum mechanics-based method for scoring protein-ligand interactions and binding affinity predictions, using quantum mechanical Hamiltonians and/or a combined quantum mechanical/molecular mechanical approach, and Poisson-Boltzmann (PB)-based solvation methods. Also provided is a method for using quantum mechanics to describe the enthalpic and solvation effects of binding. The method comprises comparing the calculated binding affinities to experimental values in order to measure the success of the method. The methods disclosed herein may further be used to score protein and drug or protein and inhibitor interactions. The present method can predict the free energy of binding of protein-ligand complexes with high accuracy so as to enable lead optimization, thus serving as a powerful tool in computational drug design.