QM/MM through the 1990s: The First Twenty Years of Method Development and Applications

Abstract

The 2013 Nobel Prize in Chemistry was awarded to the authors of the first two publications utilizing the concept of combined quantum mechanical and molecular mechanical (QM/MM) methods. In celebrating this great event in computational chemistry, we review the early development of combined QM/MM techniques and the associated events that took place through the mid-1990s. We also offer some prospects for the future development of quantum mechanical techniques for macromolecular systems.

Keywords: biomolecular interactions; computational chemistry; electronic structure; molecular mechanics; quantum mechanics.

Figure 1

Illustrations depicting the difference between the local self-consistent field and the generalized hybrid orbital methods. In the LSCF method, one (green) hybrid orbital points to the MM subsystem and is kept frozen in the QM/MM calculation, whereas the other three (red) orbitals are optimized. In the GHO method, only one hybrid orbital, dependent on the instantaneous geometry at the boundary carbon (C_b), is optimized in the SCF procedure, whereas the other three are kept frozen.

Figure 2

Papers published between 1972 and 1996 that utilized the concept of combined quantum mechanics and molecular mechanics.

Figure 3

Thermodynamic cycle illustrating the alchemical transformation to determine the difference in free energy of solvation between molecules A and B, represented by a QM/MM potential, through pure MM conduits, A′ and B′, consisting of van der Waals terms. The MM conduits could also include Coulomb terms, if desired.