Quantum Mechanics/molecular Mechanics Research Articles

Quantum Mechanics/Molecular Mechanics Simulations for Chiral-Selective Aminoacylation: Unraveling the Nature of Life

Biological phenomena are chemical reactions, which are inherently non-stopping or “flowing” in nature. Molecular dynamics (MD) is used to analyze the dynamics and energetics of interacting atoms, but it cannot handle chemical reactions involving bond formation and breaking. Quantum mechanics/molecular mechanics (QM/MM) umbrella sampling MD simulations gives us a significant clue about transition states of chemical reactions and their energy levels, which are the pivotal points in understanding the nature of life. To demonstrate the importance of this method, we present here the results of our application of it to the elucidation of the mechanism of chiral-selective aminoacylation of an RNA minihelix considered to be a primitive form of tRNA. The QM/MM MD simulation, for the first time, elucidated the “flowing” atomistic mechanisms of the reaction and indicated that the L-Ala moiety stabilizes the transition state more than D-Ala, resulting in L-Ala preference in the aminoacylation reaction in the RNA. The QM/MM method not only provides important clues to the elucidation of the origin of homochirality of biological systems, but also is expected to become an important tool that will play a critical role in the analysis of biomolecular reactions, combined with the development of artificial intelligence.

Effect of pH on azobenzene-4,4'-dicarboxylate/α-CD complex formation. Synthesis, kinetic study and molecular modeling simulations

The current study focuses on the molecular behavior of the azobenzene-4,4'-dicarboxylate/α-CD pseudorotaxane and how it is affected by changes in pH. A combination of experimental measurements and molecular simulations were used, including different computational calculations, to evaluate the kinetic and thermodynamic aspects of the formation of this mechanically bound architecture. The research involved determining the formation rate constants for these complexes at different pH values and conducting a comprehensive kinetic study. Additionally, the binding affinity and complexation reaction was analyzed using free energy profiles derived from umbrella sampling in molecular dynamics simulations. To gain a better understanding of the energetic and structural aspects of the complexes, hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) calculations were employed. The intermolecular interactions that stabilize the pseudorotaxanes were characterized using quantum theory of atoms in molecules (QTAIM) and Molecular Electrostatic Potentials (MEPs)

Combinatorial MD/QM studies to develop novel ionic liquid-based anticancer drug delivery systems with aminium derived from carbohydrates as cationic components

The main challenges in anticancer drug design include solubility in organic and aqueous phases, bioavailability, selective targeting of specific receptors, and low toxicity. Notably, solubility, bioavailability, and receptor-specific targeting are interconnected factors that significantly influence the therapeutic efficacy of anticancer drugs. The primary objective of this study is to design novel drug delivery systems based on ionic liquids. These systems incorporate structures such as N, N, N-trimethyl-2-(((2 S,3R,4 S,5 S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 H-pyran-2-yl)oxy)ethan-1-aminium (GTA) and (2 S,3R,4 S,5 S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N, N, N-trimethyltetrahydro-2 H-pyran-2-aminium (NTPA) derived from carbohydrates as cationic components, with anticancer drugs acting as anions. The goal is to investigate the effects of these novel pharmaceutical active ionic liquids on the interactions between the drugs and cell membranes. Additionally, this study examines changes in the solubility of anticancer drugs in both organic and aqueous phases after their conversion into ionic liquids. Molecular dynamics simulations (MD) and quantum mechanics calculations (QM) are employed to achieve these objectives. Known anticancer-candidate ionic liquid, such as 3-(2-((4-fluorophenyl)amino)-2-oxoethyl)-1-methyl-1 H-imidazol-3-ium-tetrafluoroborate, is considered as a reference point in our investigations. Furthermore, we aim to assess whether the direct attachment of the aminium group to the saccharide portion of the cations or the indirect attachment through a choline group significantly impacts the final properties of the designed anticancer ionic liquids. Another aim of this study is to demonstrate that QM studies need to be complemented by MD studies to provide insights into the behaviors of ionic liquids. Initially, we calculate the binding energies between cations and anions of all the ionic liquids at the B3LYP/6-311 + + G(d, p) level of theory. Subsequently, molecular dynamics simulations using GROMACS 5.2 are employed to obtain more precise information about these understudied ionic liquids. A combination of density functional theory (DFT) calculations and a solvation model based on density (SMD) is utilized to determine the solubility of free anticancer drugs and our active anticancer ionic liquids in various phases. We validate our findings by evaluating the interactions between the formulated ionic liquids and cell membranes using the DPPC model through combined MD simulations and docking procedures.

Nature of the EWS-FLI1 Oncoprotein.

The research presented in this paper focuses on the EWS-FLI1 oncoprotein, a critical factor in Ewing sarcoma, a rare and lethal cancer primarily affecting children and young adults. Through molecular dynamics and quantum mechanics analyses, the study explores the reactivity properties of six snapshots of the EWS-FLI1 oncoprotein, aiming to contribute to the development of targeted therapies. The investigation emphasizes the significance of understanding the molecular behavior of EWS-FLI1 for effective treatment development, utilizing computational methods such as density functional theory. The findings suggest that EWS-FLI1 is a compact, electrophilic protein with localized reactive sites, providing valuable insights for potential drug development and enhancing our knowledge of Ewing sarcoma for targeted treatments.

Spontaneous Generation of Alkoxide Radical from Alcohols on Microdroplets Surface.

Water microdroplets have been demonstrated to exhibit extraordinary chemical behaviors, including the abilities to accelerate chemical reactions by several orders of magnitude and to trigger reactions that cannot occur in bulk water. One of the most striking examples is the spontaneous generation of hydroxyl radical from hydroxide ions. Alcohols and alkoxide ions, being structurally similar to water and hydroxide ions, might exhibit similar behavior on microdroplets. Here, we report the spontaneous generation of alkoxide radicals from alcohols (RCH2OH) in aqueous microdroplets through quantum chemical calculations, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations, ab initio MD simulations, and mass spectrometry. Our results show that an electric field (EF) on the order of 10-1 V/Å and partial solvation at the air-water interface jointly promote the dissociation of RCH2OH into RCH2O- and H3O+ ions. QM/MM MD simulations indicate that RCH2O- can be ionized to produce RCH2O⋅ radicals on the microdroplet surface. Furthermore, partial solvation and the EF collaboratively catalyze the isomerization of the RCH2O⋅ radical into a more stable tautomer, R⋅CHOH. This study highlights the molecular mechanisms underlying the widespread generation of radicals at the microdroplet surface and provides insights into the importance of fundamental alcohol chemistry in the atmosphere.

Spontaneous Generation of Alkoxide Radical from Alcohols on Microdroplets Surface

AbstractWater microdroplets have been demonstrated to exhibit extraordinary chemical behaviors, including the abilities to accelerate chemical reactions by several orders of magnitude and to trigger reactions that cannot occur in bulk water. One of the most striking examples is the spontaneous generation of hydroxyl radical from hydroxide ions. Alcohols and alkoxide ions, being structurally similar to water and hydroxide ions, might exhibit similar behavior on microdroplets. Here, we report the spontaneous generation of alkoxide radicals from alcohols (RCH2OH) in aqueous microdroplets through quantum chemical calculations, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations, ab initio MD simulations, and mass spectrometry. Our results show that an electric field (EF) on the order of 10−1 V/Å and partial solvation at the air‐water interface jointly promote the dissociation of RCH2OH into RCH2O− and H3O+ ions. QM/MM MD simulations indicate that RCH2O− can be ionized to produce RCH2O⋅ radicals on the microdroplet surface. Furthermore, partial solvation and the EF collaboratively catalyze the isomerization of the RCH2O⋅ radical into a more stable tautomer, R⋅CHOH. This study highlights the molecular mechanisms underlying the widespread generation of radicals at the microdroplet surface and provides insights into the importance of fundamental alcohol chemistry in the atmosphere.

End Group Effects on Anion Binding in Tetraglycine Peptide: A Computational Study.

The importance of anions in various processes has led to a search for molecules that can effectively recognize and interact with these anions. This study explores how the tetraglycine [(Gly)4] peptide in its zwitterionic, neutral, and terminally capped forms acts as a receptor for H2PO4 - and HSO4 - anions within the framework of supramolecular host-guest chemistry. Using molecular dynamics (MD) simulations, we obtained the conformations of the receptor-anion complexes. Density functional theory (DFT), quantifies the complexes' interaction energies in both gas and solvent phases. Proton transfer within the zwitterionic complex with H2PO4 - anion alters peptide charge distribution, affecting its conformation and binding site arrangement, as analysed by quantum mechanics/molecular mechanics (QM/MM) methods. Symmetry-adapted perturbation theory (SAPT) and noncovalent interactions analysis highlight the role of electrostatic interactions in these receptor-anion complexes. It emphasizes the key interactions such as N-H⋅⋅⋅⋅O and O-H⋅⋅⋅O=C between the peptide backbone and anions and elucidates the molecular recognition mechanism driven by crucial noncovalent interactions. The termination of the peptide's end groups modulates anion binding sites from the backbone to the charged N-terminal, resulting in distinct binding sites. Our findings provide insights for designing peptides tailored to function as anion receptors in diverse supramolecular chemistry applications.

Nonadiabatic Excited-State Molecular Dynamics with an Explicit Solvent: NEXMD-SANDER Implementation.

In this article, the nonadiabatic excited-state Molecular dynamics (NEXMD) package is linked with the SANDER package, provided by AMBERTOOLS. The combination of these software packages enables the simulation of photoinduced dynamics of large multichromophoric conjugated molecules involving several coupled electronic excited states embedded in an explicit solvent by using the quantum/mechanics/molecular mechanics (QM/MM) methodology. The fewest switches surface hopping algorithm, as implemented in NEXMD, is used to account for quantum transitions among the adiabatic excited-state simulations of the photoexcitation and subsequent nonadiabatic electronic transitions, and vibrational energy relaxation of a substituted polyphenylenevinylene oligomer (PPV3-NO2) in vacuum and methanol as an explicit solvent has been used as a test case. The impact of including specific solvent molecules in the QM region is also analyzed. Our NEXMD-SANDER QM/MM implementation provides a useful computational tool to simulate qualitatively solvent-dependent effects, like electron transfer, stabilization of charge-separated excited states, and the role of solvent reorganization in the molecular optical properties, observed in solution-based spectroscopic experiments.

Investigating the Substrate Oxidation Mechanism in Lytic Polysaccharide Monooxygenase: H2O2- versus O2-Activation.

Lytic polysaccharide monooxygenases (LPMOs) form a copper-dependent family of enzymes classified under the auxiliary activity (AA) superfamily. The LPMOs are known for their boosting of polysaccharide degradation through oxidation of the glycosidic bonds that link the monosaccharide subunits. This oxidation has been proposed to be dependent on either O2 or H2O2 as cosubstrate. Theoretical investigations have previously supported both mechanisms, although this contrasts with recent experiments. A possible explanation is that the theoretical results critically depend on how the Cu active site is modeled. This has also led to different results even when employing only H2O2 as cosubstrate. In this paper, we investigate both the O2- and H2O2-driven pathways, employing LsAA9 as the underlying LPMO and a theoretical model based on a quantum mechanics/molecular mechanics (QM/MM) framework. We ensure to consistently include all residues known to be important by using extensive QM regions of up to over 900 atoms. We also investigate several conformers that can partly explain the differences seen in previous studies. We find that the O2-driven reaction is unfeasible, in contrast with our previous QM/MM calculations with smaller QM regions. Meanwhile, the H2O2-driven pathway is feasible, showing that for LsAA9, only H2O2 is a viable cosubstrate as proposed experimentally.

Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.

γ-Secretase plays a crucial role in producing disease-related amyloid-β proteins by cleaving the amyloid precursor protein (APP). The enzyme employs its catalytic dyad containing two aspartates (Asp257 and Asp385) to hydrolyze the substrate by a general acid-base catalytic mechanism, necessitating monoprotonation of the two aspartates for efficient hydrolysis. However, the precise protonation states of the aspartates remain uncertain. In this study, we employed a multiscale computational approach to investigate the dependence of the catalytic efficiency of γ-secretase on the protonation states of its catalytic dyad. Over 200 ms unbiased atomistic simulations of the substrate-enzyme complex reveal diverse orientations of the scissile bond of the bound substrate and accessible structural ensembles of the catalytic dyad with Asp257-Asp385 distances fluctuating between 4 and 10 Å. With a quantum mechanics/molecular mechanics (QM/MM) approach accelerated by enhanced sampling techniques, we find that the first step of the hydrolysis reaction, i.e., the formation of a gem-diol intermediate, experiences a higher reaction barrier by ∼2 kcal/mol when Asp385 is protonated. Furthermore, we find that Arg269 of the enzyme is most likely responsible for this preference of the protonation state: its basic side chain is spatially close to that of Asp257 and specifically stabilizes the transition state electrostatically when Asp257 is protonated. Collectively, our study suggests that Asp257 is likely the favored protonation site for APP cleavage by γ-secretase.

Origins of Catalysis in Non-Heme Fe(II)/2-Oxoglutarate-Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides.

Histone lysine demethylase 4A (KDM4A), a non-heme Fe(II)/2-oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri-methylated lysine residues at the 9, 27, and 36 positions of histone H3 (H3K9me3, H3K27me3, and H3K36me3). These methylated residues show contrasting transcriptional roles; therefore, understanding KDM4A's catalytic mechanisms with these substrates is essential to explain the factors that control the different sequence-dependent demethylations. In this study, we use molecular dynamics (MD)-based combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate determinants of KDM4A catalysis with H3K9me3, H3K27me3 and H3K36me3 substrates. In KDM4A-H3(5-14)K9me3 and KDM4A-H3(23-32)K27me3 ferryl complexes, the O-H distance positively correlates with the activation barrier of the rate-limiting step, however in the KDM4A-H3(32-41)K36me3, no direct one-to-one relationship was found implying that the synergistic effects between the geometric parameters, second sphere interactions and the intrinsic electric field contribute for the effective catalysis for this substrate. The intrinsic electric field along the Fe-O bond changes between the three complexes and shows a positive correlation with the HAT activation barrier, suggesting that modulating electric field can be used for fine engineering KDM catalysis with a specific substrate. The results reveal how KDM4A uses a combination of strategies to enable near equally efficient demethylation of different H3Kme3 residues.

The Reaction Mechanism and Rates at Ru Single-Atom Catalysts for Hydrogenation of Biomass BHMF to Produce BHMTHF for Renewable Polymers.

Realizing high selectivity for producing biodegradable 2,5-bis(hydroxymethyl)tetrahydrofuran (BHMTHF) for renewable polymers from 5-hydroxymethylfurfural (HMF) biomass through ring hydrogenation on single-atom catalysts poses a considerable challenge due to the complexity of HMF functional groups and the difficulty of H2 dissociation. We developed a detailed reaction mechanism based on ab initio molecular dynamics (AIMD) and quantum mechanics (QM) to find that Ru single-atom catalysts can simultaneously dissociate H2 and perform the ring hydrogenation of biomass-derived 2,5-bis(hydroxymethyl)furan (BHMF) to produce biodegradable BHMTHF, with a free energy barrier of 0.82 eV. The unique property of Ru single-atom sites enables H2 to dissociate easily on a single active site of Ru to participate directly in the reaction without diffusion. Furthermore, our predicted reaction rate from microkinetic analysis indicates that ring hydrogenation and side-chain hydrogenolysis are much faster than ring-opening hydrogenation over the range of 300-550 K. The product BHMTHF dominates with a selectivity of 98.9% at 300 and 78.4% at 550 K (the second product is 5-methylfurfural (5-MFA)). This study underscores the unique effectiveness of Ru single atoms in ring hydrogenation reactions using H2 as the hydrogen source, offering insights for the design of single-atom catalysts for other biomass reactions.

Electron Attachment to the Nucleobase Uracil in Diethylene Glycol: The Signature of a Doorway.

The cellular environment plays a significant role in low energy electron-mediated radiation damage to genetic materials. In this study, we have modeled the effect of the bulk medium on electron attachment to nucleobases in diethylene glycol (DEG) using uracil as a test case, in accordance with recent experimental work on the observation of dissociative quasi-free electron attachment to nucleoside via excited anion radical in solution (in DEG). Our EOM-CCSD-based quantum mechanical/molecular mechanical (QM/MM) simulations indicate that the electron scavenging by uracil in DEG is much slower than that observed in the aqueous medium due to its viscosity. This work also establishes that a doorway mechanism exists in uracil microsolvated and bulk solvated with DEG, with the dipole-bound state and solvent-bound state acting as doorway states, respectively.

Computational and experimental analysis of Luteolin-β-cyclodextrin supramolecular complexes: Insights into conformational dynamics and phase solubility

Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis. Microsecond timescale MD simulations yielded insights into LuT-CD interactions. The binding affinity between LuT and selected β-CDs was assessed by calculating the binding free energy using MM-PBSA and umbrella sampling simulations. The MM-PBSA results indicated that Heptakis-O-(2-hydroxypropyl)-β-CD (HP-β-CD) (−82.59+/-11.67 kJ/mol) and Di-O-methyl-β-CD (DM-β-CD) (−54.01+/-11.07 kJ/mol) exhibited good binding affinity for LuT. Subsequently, derivative screening of HP-β-CD revealed that only 2-HP-β-CD (HP-β-CD-1)/LuT (−21.38 kJ/mol) displayed a superior binding free energy (obtained from umbrella sampling) than HP-β-CD/LuT (−16.55 kJ/mol) inclusion complex. We conducted QM calculations on the top three inclusion complexes namelly HP-β-CD, DM-β-CD, and HP-β-CD-1 employing wB97X-D/6–311 + G(d,p) model chemistry to strengthen the MM results. The computational analysis aligns with experimental findings (phase solubility analysis), validating HP-β-CD-1 as most effective cavitand molecule for improving the solubility of LuT. This study offers critical structural insights for developing novel HP-β-CD derivatives with enhanced host capacity to encapsulate guest molecules efficiently.

Theoretical investigation on the surrounding effects of second-order nonlinear properties for (N^C^N)Pt(II)Cl complexes

Pt(II) complexes are widely used as nonlinear optical (NLO) materials. The geometric and electronic structures, second-order NLO property and UV–Vis absorption spectra of (N^C^N)Pt(II)Cl complexes (1–4) N^C^N binding by central benzene and two lateral N-heterocycles) are evaluated by density functional theory (DFT) and time-dependent DFT calculations. The detailed environmental effect of total first hyperpolarizability (βtot) in the solution and crystal phases is simulated by polarized continuum model (PCM) and quantum mechanics/molecular mechanics (QM/MM) method, respectively. The results highlight that the complex 3 exhibits largest βtot value in the gas, solution and crystal phases which can be attributed to the higher electron π-delocalization of ligands. Further, an evident red shift towards longer wavelength is observed for the complex 3. The origin of larger βtot value can be reasonably interpreted by the two-level model. In addition, the surrounding exerts an important influence on modulating second-order NLO properties. The solvent effect results in the larger βtot value than that of gas phase. The intermolecular interaction plays an important role in crystal phase. The formation of dimer can reduce the βtot value in comparison with the βtot value of the monomer in the crystal phase, because the centrosymmetric configuration of dimer implies a decrease of dipole moment (μ) in contrast to the large μ value of monomer. It is expected that this work will provide some guidance for designing Pt(II) NLO materials.

Quantum mechanics/molecular mechanics (QM/MM) methods in drug design: a comprehensive review of development and applications

The integration of quantum mechanics (QM) and molecular mechanics (MM) methods, known as QM/MM, has emerged as a powerful computational approach in drug design. This hybrid technique combines the accuracy of QM calculations for the reactive region with the computational efficiency of MM methods for the surrounding environment. QM/MM methods have proven invaluable in studying chemical reactions, exploring enzyme mechanisms, and investigating ligand-protein interactions, all of which are crucial for rational drug design. This review provides a comprehensive overview of the QM/MM methodology, its theoretical foundations, and its applications in various aspects of drug design. We discussed the key components, such as QM and MM region partitioning, link atom schemes, and boundary treatments. Additionally, we highlight recent advancements and challenges in QM/MM methods, including polarizable force fields, implicit solvation models, and enhanced sampling techniques. Furthermore, we present illustrative examples showcasing the successful application of QM/MM methods in lead optimization, virtual screening, and the elucidation of biochemical mechanisms relevant to drug targets. Finally, we provide perspectives on future developments and the potential impact of QM/MM methods on the drug discovery pipeline.

Dissociation Energies via Embedding Techniques.

Due to the large number of interactions, evaluating interaction energies for large or periodic systems results in time-consuming calculations. Prime examples are liquids, adsorbates, and molecular crystals. Thus, there is a high demand for a cheap but still accurate method to determine interaction energies and gradients. One approach to counteract the computational cost is to fragment a large cluster into smaller subsystems, sometimes called many-body expansion, with the fragments being molecules or parts thereof. These subsystems can then be embedded into larger entities, representing the bigger system. In this work, we test several subsystem approaches and explore their limits and behaviors, determined by calculations of trimer interaction energies. The methods presented here encompass mechanical embedding, point charges, polarizable embedding, polarizable density embedding, and density embedding. We evaluate nonembedded fragmentation, QM/MM (quantum mechanics/molecular mechanics), and QM/QM (quantum mechanics/quantum mechanics) embedding theories. Finally, we make use of symmetry-adapted perturbation theory utilizing density functional theory for the monomers to interpret the results. Depending on the strength of the interaction, different embedding methods and schemes prove favorable to accurately describe a system. The embedding approaches presented here are able to decrease the interaction energy errors with respect to full system calculations by a factor of up to 20 in comparison to simple/unembedded approaches, leading to errors below 0.1 kJ/mol.

The Interaction Mechanism Between C14-Polyacetylene Compounds and the Rat TRPA1 Receptor: An In Silico Study.

Polyacetylene (PA) compounds, as natural products, exhibit remarkable properties and distinctive chemical activities. Three structurally similar C14-PA compounds-Echinophorin D, Echinophorin B, and Echinophorin A-extracted from plants demonstrate varying biological activities on the Transient Receptor Potential Channel A1 (TRPA1) protein, which belongs to the TRP (Transient Receptor Potential) family. In the current study, we investigated the binding modes of these three PA compounds with TRPA1 using molecular dynamics (MD), molecular docking, binding free energy calculations, and quantum mechanics/molecular mechanics (QM/MM) methods. Initially, a putative binding site (site-II) in TRPA1 was identified for these compounds; Echinophorin B was found to stabilize the upward A-loop of TRPA1, which is critical for its activation. Furthermore, the binding affinity calculations of PA compounds through molecular fragment decomposition indicate that the arrangement of two triple bonds and one double bond in C14-PA compounds is vital for regulating TRPA1 bioactivity. Additionally, the lipophilic and electronic properties of the three molecules were analyzed in relation to binding affinity, establishing a correlation between TRPA1 activity and these molecular properties.

Assessing the Partial Hessian Approximation in QM/MM-Based Vibrational Analysis.

The partial Hessian approximation is often used in vibrational analysis of quantum mechanics/molecular mechanics (QM/MM) systems because calculating the full Hessian matrix is computationally impractical. This approach aligns with the core concept of QM/MM, which focuses on the QM subsystem. Thus, using the partial Hessian approximation implies that the main interest is in the local vibrational modes of the QM subsystem. Here, we investigate the accuracy and applicability of the partial Hessian vibrational analysis (PHVA) approach as it is typically used within QM/MM, i.e., only the Hessian belonging to the QM subsystem is computed. We focus on solute-solvent systems with small, rigid solutes. To separate two of the major sources of errors, we perform two separate analyses. First, we study the effects of the partial Hessian approximation on local normal modes, harmonic frequencies, and harmonic IR and Raman intensities by comparing them to those obtained using full Hessians, where both partial and full Hessians are calculated at the QM level. Then, we quantify the errors introduced by QM/MM used with the PHVA by comparing normal modes, frequencies, and intensities obtained using partial Hessians calculated using a QM/MM-type embedding approach to those obtained using partial Hessians calculated at the QM level. Another aspect of the PHVA is the appearance of normal modes resembling the translation and rotation of the QM subsystem. These pseudotranslational and pseudorotational modes should be removed as they are collective vibrations of the atoms in the QM subsystem relative to a frozen MM subsystem and, thus, not well-described. We show that projecting out translation and rotation, usually done for systems in isolation, can adversely affect other normal modes. Instead, the pseudotranslational and pseudorotational modes can be identified and removed.

Constrained nuclear-electronic orbital QM/MM approach for simulating complex systems with quantum nuclear delocalization effects incorporated

The hybrid quantum mechanics/molecular mechanics (QM/MM) approach, which combines the accuracy of QM methods with the efficiency of MM methods, is widely used in the study of complex systems. However, past QM/MM implementations often neglect or face challenges in addressing nuclear quantum effects, despite their crucial role in many key chemical and biological processes. Recently, our group developed the constrained nuclear-electronic orbital (CNEO) theory, a cost-efficient approach that accurately addresses nuclear quantum effects, especially quantum nuclear delocalization effects. In this work, we integrate CNEO with the QM/MM approach through the electrostatic embedding scheme and apply the resulting CNEO QM/MM to two hydrogen-bonded complexes. We find that both solvation effects and nuclear quantum effects significantly impact hydrogen bond structures and dynamics. Notably, in the glutamic acid–glutamate complex, which mimics a common low barrier hydrogen bond in biological systems, CNEO QM/MM accurately predicts nearly equal proton sharing between the two residues. With an accurate description of both quantum nuclear delocalization effects and environmental effects, CNEO QM/MM is a promising new approach for simulating complex chemical and biological systems.