Calculation of Electrostatic Interaction Energies in Molecular Dimers from Atomic Multipole Moments Obtained by Different Methods of Electron Density Partitioning ANATOLIY VOLKOV, PHILIP COPPENS Department of Chemistry, State University of New York at Buffalo, Buffalo, New York, 14260-3000 Received 1 September 2003; Accepted 23 November 2003 Abstract: Accurate and fast evaluation of electrostatic interactions in molecular systems is still one of the most challenging tasks in the rapidly advancing field of macromolecular chemistry, including molecular recognition, protein modeling and drug design. One of the most convenient and accurate approaches is based on a Buckingham-type approximation that uses the multipole moment expansion of molecular/atomic charge distributions. In the mid-1980s it was shown that the pseudoatom model commonly used in experimental X-ray charge density studies can be easily combined with the Buckingham-type approach for calculation of electrostatic interactions, plus atom–atom potentials for evaluation of the total interaction energies in molecular systems. While many such studies have been reported, little attention has been paid to the accuracy of evaluation of the purely electrostatic interactions as errors may be absorbed in the semiempirical atom–atom potentials that have to be used to account for exchange repulsion and dispersion forces. This study is aimed at the evaluation of the accuracy of the calculation of electrostatic interaction energies with the Buckingham approach. To eliminate experimental uncertainties, the atomic moments are based on theoretical single- molecule electron densities calculated at various levels of theory. The electrostatic interaction energies for a total of 11 dimers of -glycine, N-acetylglycine and L-(+)-lactic acid structures calculated according to Buckingham with pseudoatom, stockholder and atoms-in-molecules moments are compared with those evaluated with the Morokuma– Ziegler energy decomposition scheme. For -glycine a comparison with direct “pixel-by-pixel” integration method, recently developed Gavezzotti, is also made. It is found that the theoretical pseudoatom moments combined with the Buckingham model do predict the correct relative electrostatic interactions energies, although the absolute interaction energies are underestimated in some cases. The good agreement between electrostatic interaction energies computed with Morokuma–Ziegler partitioning, Gavezzotti’s method, and the Buckingham approach with atoms-in-molecules moments demonstrates that reliable and accurate evaluation of electrostatic interactions in molecular systems of considerable complexity is now feasible. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 921–934, 2004 Key words: electron density; electrostatic interaction energy; density partitioning; atomic moments; molecular moments; pseudoatom model Introduction According to the Morokuma–Ziegler energy partitioning scheme 1–3 the total intermolecular monomer-monomer interaction energy E int is written as E int = E es + E Pauli + E oi (1) where E es is the electrostatic interaction energy, E Pauli is the Pauli, or exchange repulsion, which accounts for steric repulsion, and E oi (orbital interaction energy) includes charge transfer and polariza- tion effects that occur upon the relaxation of the interacting system to its final state. This energy decomposition scheme is similar to the Kitaura–Morokuma analysis, 4,5 which explicitly partitions the Correspondence to: Dr. A. Volkov; e-mail: volkov@chem.buffalo.edu This article includes Supplementary Material available from the authors upon request or via the Internet at http://www.interscience.wiley.com/ jpages/0192-8651/suppmat. © 2004 Wiley Periodicals, Inc.