Limiting assumptions in molecular modeling: electrostatics

Abstract

Molecular mechanics attempts to represent intermolecular interactions in terms of classical physics. Initial efforts assumed a point charge located at the atom center and coulombic interactions. It is been recognized over multiple decades that simply representing electrostatics with a charge on each atom failed to reproduce the electrostatic potential surrounding a molecule as estimated by quantum mechanics. Molecular orbitals are not spherically symmetrical, an implicit assumption of monopole electrostatics. This perspective reviews recent evidence that requires use of multipole electrostatics and polarizability in molecular modeling.

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Acknowledgments

Many have contributed to what we have collectively attempted in computer-aided molecular design; my thanks for sharing the dream. In particular I need to thank my colleagues, Drs. Xiange Zheng, for her MD simulations comparing monopole force fields with AMOEBA, and Dan Kuster for his analysis of high-resolution protein helices. Many (too numerous to mention) have generously pointed out critical mistakes along my ultimate path to humility. This includes the referees of the first draft of this manuscript. A long association with Prof. Andy Vinter (a founding editor of JCAMD) opened my eyes to the problems with monopole electrostatics, and generated a noticeable avoidance of modeling nucleic acids and membranes on my part due to their high charge density. In particular, however, my proximity to Prof. Jay Ponder during his development of AMOEBA has taught me the necessity to swim upstream, i. e. to do what is scientifically justified without concern for the myopia of the field. Hopefully, the validation of AMOEBA has reached an acceptable level of maturity, and the molecular-modeling community can reap the benefits in its application. Discussion on the problems of representing electrostatics with Prof. Anthony Stone of Cambridge University has clarified many of the issues. My thanks also to Prof. Rino Ragno and the Sapienza Università di Roma for being my host during the preparation of this perspective. Finally, my thanks to the Editors of JCAMD for providing me this opportunity to pontificate, so appropriate considering my location in Rome.

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Correspondence to Garland R. Marshall.

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Marshall, G.R. Limiting assumptions in molecular modeling: electrostatics. J Comput Aided Mol Des 27, 107–114 (2013). https://doi.org/10.1007/s10822-013-9634-x

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Keywords

  • Electrostatics
  • Multipole
  • Dipole
  • Quadrupole
  • Polarizability
  • AMOEBA
  • Affinity prediction
  • Structure-based drug design