Born–Oppenheimer Ab Initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions

Abstract

There are two key requirements for reliably simulating enzyme reactions: one is a reasonably accurate potential energy surface to describe the bond forming/breaking process as well as to adequately model the heterogeneous enzyme environment; the other is to perform extensive sampling since an enzyme system consists of at least thousands of atoms and its energy landscape is very complex. One attractive approach to meet both daunting tasks is Born-Oppenheimer ab initio QM/MM molecular dynamics simulation (aiQM/MM-MD) with umbrella sampling. In this chapter, we describe our recently developed pseudobond Q-Chem–Amber interface, which employs a combined electrostatic-mechanical embedding scheme with periodic boundary condition and the particle mesh Ewald method for long-range electrostatics interactions. In our implementation, Q-Chem and the sander module of Amber are combined at the source code level without using system calls, and all necessary data communications between QM and MM calculations are achieved via computer memory. We demonstrate the applicability of this pseudobond Q-Chem–Amber interface by presenting two examples, one reaction in aqueous solution and one enzyme reaction. Finally, we describe our established aiQM/MM-MD enzyme simulation protocol, which has been successfully applied to study more than a dozen enzymes.

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

“…The most crucial tasks are the construction of both a simulation protocol and an efficient interface between the corresponding force field and QM software . There are three essential aspects to consider in studying enzyme mechanisms by QM/MM models: (i) how the interaction between QM and MM regions is treated, (ii) how to cross the covalent bonds between atoms at the QM/MM boundary, and (iii) how to compute the total energy.…”

“…According to this approach, Gao and coworkers developed the general hybrid orbital (GHO) method on the boundary atoms to be used within the SQM, ab‐initio , and DFT methods. Later, the concept has been further developed into a framework called pseudobonds where each atom at the outer boundary (MM region) is described in the QM region by a pseudoatom with a charge of +7, seven valence electrons, parameterized STO‐2G basis set, and angular‐momentum‐independent effective core potentials (ECP). Capping pseudoatoms are available for CN and CC bonds of protein backbones and nucleic acid bases using B3LYP/6–31G*.…”

“…In the past decades, Zhang with his coworkers demonstrated how valuable the QM/MM/MD simulations can be for the description of enzymatic reactions based on the subtractive QM/MM scheme . In most of their studies, the popular DFT functional B3LYP is used with the Stuttgart ECP basis set for all the transition‐metals and the 6–31G* basis set for all other QM atoms .…”

“…Additionally, each atom at the inner boundary is described in the QM region by a pseudoatom (See section 2.2). For their purposes, Zhang and coworkers implemented a modification of the particle mesh Ewald (PME) method called dual‐focal ab‐initio QM/MM‐PME. It takes advantage of the fact that the differences originating from summing up fitted charges (i.e., an approximate ESP charge distribution representing the density in image boxes) instead of the original charges are very small at distances as large as the unit cell.…”

Two symmetric arginine residues play distinct roles in Thermus thermophilus Argonaute DNA guide strand-mediated DNA target cleavage

“…All other atoms were described by the same molecular mechanical force field used in the classical MD simulations. In our QM/MM calculations, the recently developed periodic boundary condition with Ewald method was applied to reliably describe the long-range interactions and dynamics (56,(120)(121)(122). The 12-Å cutoff was used for vdW and short-range PME interactions, and there was no cutoff for electrostatic interactions between QM and MM regions.…”