Three-Layer Multiscale Approach Based on Extremely Localized Molecular Orbitals to Investigate Enzyme Reactions

Abstract

Quantum mechanics/molecular mechanics (QM/MM) calculations are widely used embedding techniques to computationally investigate enzyme reactions. In most QM/MM computations, the quantum mechanical region is treated through density functional theory (DFT), which offers the best compromise between chemical accuracy and computational cost. Nevertheless, to obtain more accurate results, one should resort to wave function-based methods, which however lead to a much larger computational cost already for relatively small QM subsystems. To overcome this drawback, we propose the coupling of our QM/ELMO (quantum mechanics/extremely localized molecular orbital) approach with molecular mechanics, thus introducing the three-layer QM/ELMO/MM technique. The QM/ELMO strategy is an embedding method in which the chemically relevant part of the system is treated at the quantum mechanical level, while the rest is described through frozen ELMOs. Since the QM/ELMO method reproduces results of fully QM computations within chemical accuracy and with a much lower computational effort, it can be considered a suitable strategy to extend the range of applicability and accuracy of the QM/MM scheme. In this paper, other than briefly presenting the theoretical bases of the QM/ELMO/MM technique, we will also discuss its validation on the well-tested deprotonation of acetyl coenzyme A by aspartate in citrate synthase.

Initial Maximum Overlap Method for Large Systems by the Quantum Mechanics/Extremely Localized Molecular Orbital Embedding Technique

“…In particular, by exploiting the recent inclusion of the outer molecular mechanics layer in the framework of the QM/ ELMO approach, 106 we initially carried out IMOM/ELMO/ MM computations with (i) the QM region practically consisting only of the isoalloxazine triple ring of flavin mononucleotide (see the right panel of Figure 3), (ii) the ELMO subsystem comprising the side chain of FMN (see again the right panel of Figure 3) and all the atoms of flavodoxin within a 3.0 Å radius from any atom of the substrate, and (iii) the MM subunit corresponding to the rest of the protein and the surrounding water molecules. To evaluate the effects of long-range electrostatic interactions, the external MM region was then neglected, and simple IMOM/ ELMO calculations were performed exploiting the same IMOM/ELMO partitioning scheme adopted for the abovedescribed IMOM/ELMO/MM computations.…”

Linear response properties of solvated systems: a computational study

“…This problem can be solved by three-layer approaches, where the largest part of the environment, usually the farthest from the solute, is described by means of classical force fields. 21,[35][36][37][38][39] In this way, within a small portion of the system most interactions are treated at the QM level, whereas longrange contributions are retained at the classical level only, providing a physically consistent picture. In this work, we present a computational investigation of linear response properties of two organic systems, namely para-nitroaniline (PNA) and benzonitrile (PhCN), dissolved in 1,4-dioxane (DIO), acetonitrile (ACN), and tetrahydrofuran (THF).…”

Climbing Jacob’s Ladder of Structural Refinement: Introduction of a Localized Molecular Orbital-Based Embedding for Accurate X-ray Determinations of Hydrogen Atom Positions

“…Along this line, another possibility considered in this work is the coupling of HAR with the more recent QM/ELMO/MM technique, a three-layer approach where the outermost region is treated by means of classical molecular mechanics (MM). 54 As in a traditional Hirshfeld atom refinement, also for the new version of the method proposed in this work, it is necessary to define a reference crystal unit, which must correspond at least to the asymmetric unit of the crystal structure that one wants to refine. After this preliminary definition, the new embedded-HAR technique consists of the following self-consistent cycle:…”

“…Instead of simply using a cluster of point charges, in the refinement process we propose to mimic the crystal environment of the reference unit at a fully quantum mechanical level by exploiting a novel embedding approach: the quantum mechanics/extremely localized molecular orbital (QM/ELMO) method, − namely, a technique that successfully enables treating the most important (or chemically relevant) region of the system under examination at a higher level of theory (HF, DFT, or post-HF levels), while the remaining part is described through frozen extremely localized molecular orbitals previously transferred from the recently constructed ELMO libraries or from proper tailor-made model molecules. Along this line, another possibility considered in this work is the coupling of HAR with the more recent QM/ELMO/MM technique, a three-layer approach where the outermost region is treated by means of classical molecular mechanics (MM) …”

“…In our case, instead of a simple QM calculation or a QM computation with an embedding cluster of point charges, we perform a QM/ELMO or QM/ELMO/MM calculation in which the chosen reference crystal unit is fully treated at the QM level (HF, DFT, or post-HF), while the crystal environment (i.e., the other symmetry-generated units within a given radius from any atom of the reference unit) is described through transferred extremely localized molecular orbitals and, in the QM/ELMO/MM case, also through a classical MM force field (see Figure ). This allows a complete or partial quantum mechanical treatment of the embedding due to the crystal environment (see the Supporting Information for more details about the QM/ELMO − and QM/ELMO/MM methods).…”