Abstract: The present invention addresses the need for a fast, accurate and broadly applicable method of computing accurate partial atomic charges in the context of molecular calculations. The method uses the electronegativity equalization approach and is parameterized to reproduce ab initio molecular electrostatic potentials. It uses a new algorithm to ensure correct treatment of molecules having multiple resonance forms that contribute significantly to the electronic structure. The method will be useful in a variety of computational chemistry applications, including structure-based drug design, and the algorithm for identifying alternate resonance forms of molecules has additional applications in molecular modeling and chemical informatics.