QM/MM Energy Decomposition Using the Interacting Quantum Atoms Approach.

Roberto López,Angel Martín-Pendás,Natalia Díaz,Dimas Suárez,Evelio Francisco

doi:10.1021/acs.jcim.1c01372

Roberto López, Angel Martín-Pendás + Show 3 more

Open Access

https://doi.org/10.1021/acs.jcim.1c01372

Copy DOI

Abstract

The interacting quantum atoms (IQA) method decomposes the quantum mechanical (QM) energy of a molecular system in terms of one- and two-center (atomic) contributions within the context of the quantum theory of atoms in molecules. Here, we demonstrate that IQA, enhanced with molecular mechanics (MM) and Poisson–Boltzmann surface-area (PBSA) solvation methods, is naturally extended to the realm of hybrid QM/MM methodologies, yielding intra- and inter-residue energy terms that characterize all kinds of covalent and noncovalent bonding interactions. To test the robustness of this approach, both metal–water interactions and QM/MM boundary artifacts are characterized in terms of the IQA descriptors derived from QM regions of varying size in Zn(II)– and Mg(II)–water clusters. In addition, we analyze a homologous series of inhibitors in complex with a matrix metalloproteinase (MMP-12) by carrying out QM/MM–PBSA calculations on their crystallographic structures followed by IQA energy decomposition. Overall, these applications not only show the advantages of the IQA QM/MM approach but also address some of the challenges lying ahead for expanding the QM/MM methodology.

Highlights

Pure quantum mechanical (QM) or hybrid quantum mechanical/molecular mechanical (QM/molecular mechanics (MM)) methods are indispensable tools in biomolecular modeling given that, in principle, they are systematically improvable, provide a high degree of transferability, and, in most cases, they include all the effects required for a proper description of chemical reactions, noncovalent interactions, ligand chelation to metals, etc
The extension of the interacting quantum atoms (IQA) methodology presented in this work is a step forward toward the detailed energy decomposition of large biomolecular systems described with quantum mechanical/molecular mechanical (QM/MM) methods, yielding valuable information about energy changes at the residue level
Taking advantage of the IQA characteristics as a real-space energy decomposition that splits the QM energy into atomic and diatomic contributions, we have shown that the QM−MM electrostatic interaction is readily included as one more pairwise IQA term

Summary

Introduction

Pure quantum mechanical (QM) or hybrid quantum mechanical/molecular mechanical (QM/MM) methods are indispensable tools in biomolecular modeling given that, in principle, they are systematically improvable, provide a high degree of transferability, and, in most cases, they include all the effects required for a proper description of chemical reactions, noncovalent interactions, ligand chelation to metals, etc. In this way, QM methods are capable of overcoming some of the limitations of the physically based MM methods that generally do not incorporate an explicit representation of electronic effects like polarization and charge transfer. The partitioning of QM/MM energies including environmental effects are still relatively scarce and, it would be interesting to expand the applicability of the various EDA techniques in order to treat large systems described by QM/MM Hamiltonians

Objectives

Results

Conclusion