(225g) Implementation of Quantum Mechanics/Coarse-Grained Molecular Mechanics (QM/CG-MM)

Advances in understanding of complex biochemical processes using molecular simulations critically depend on the availability of accurate and computationally efficient force fields, enabling efficient exploration of the configurational space. As the computational cost of classical all-atom (AA) force fields becomes increasingly high and insurmountable for certain classes of proteins (e.g., actin) or lipid membranes, bottom-up coarse-graining (CG) models offer a viable alternative. The multiscale coarse-graining methodology (MSCG),¹ based on the variational principle of force matching, enables access to longer time and larger length scales through the reduction of the number of degrees of freedom with minimal loss of accuracy, as has been demonstrated for a disparate set of systems ranging from ionic liquids to lipids.

Current classical AA and CG methods are inherently limited to processes that preserve the topology of molecules involved, and thus cannot describe chemical bond breaking and formation. This limitation has been partially lifted with the advent of the Quantum Mechanics/Molecular Mechanics (QM/MM) method, which treats a small region undergoing chemical transformations quantum mechanically, whereas the rest of the system is described classically. However, the large number of MM degrees of freedom together with the high computational cost of QM energy evaluations render this method unsuitable for large protein molecules.

Sinitskiy and Voth² proposed the QM/CG-MM theory, which holds promise to surmount QM/MM limitations by coarse-graining the MM part. In this work, we evaluate one implementation of this method based on the MSCG theory. We consider two model systems: QM CCl₄ embedded in (CG-) MM CCl₄ (non-reactive non-polar system) and the reaction of tert-butyl hypochlorite with benzyl radical in (CG-)MM CCl₄, for which the experimentally measured reaction rate constant is available³ to determine the method’s accuracy. We assess the method’s performance relative to QM/MM by comparing radial distribution functions and the potential of mean force. Finally, we discuss strategies to extend the method to polar solvents.

References:

1. Izvekov, S., & Voth, G. A. (2005). A multiscale coarse-graining method for biomolecular systems. The Journal of Physical Chemistry B, 109(7), 2469-2473.
2. Sinitskiy, A. V., & Voth, G. A. (2018). Quantum mechanics/coarse-grained molecular mechanics (QM/CG-MM). The Journal of chemical physics, 148(1), 014102.
3. Zavitsas, A. A., & Blank John, D. (1972). Kinetics of the free-radical chain chlorination of hydrocarbons by tert-butyl hypochlorite. Journal of the American Chemical Society, 94(13), 4603-4608.