Mechanical Molecular Dynamics Research Articles

Structural Dynamics in the Presence of Water of Graphene Bilayers with Defects.

The dynamics of a bilayer of graphene containing one mono-vacancy in the top layer has been investigated in the framework of DFTB in the absence and in the presence of water. Due to the speed of the code, we can describe details of the behavior, which are not directly accessible experimentally and cannot be treated by DFT or classical molecular dynamics. The presence of water enhances the displacement of carbon atoms in the perpendicular direction to the surface. Our results explain very well a variety of experimental findings. In particular, the stabilization of the Jahn-Teller distortion by hydrogenation of one of the carbon atoms at the edge of a mono-vacancy has been elucidated. This work is the first analysis of the behavior of a graphene vacancy at room temperature in contact with water based on a quantum mechanical molecular dynamics method, where both graphene and solvent are treated at the same level.

Chemical scanning of atomic oxygen at the gas-liquid interface of a NaCl solution via quantum mechanics/molecular mechanics molecular dynamics simulations

Atmospheric pressure plasmas can serve as double phase reactors to produce plasma activated water for water treatment. However, the physical-chemical processes involving plasma-supplied atomic oxygen and reactive oxygen species in an aqueous solution remain unclear. In this work, quantum mechanics (QM)/molecular mechanics (MM) molecular dynamics simulations (MDs) have been performed to directly observe the chemical reactions occurring between atomic oxygen and a NaCl solution at the gas-liquid interface using a model containing 10,800 atoms. During simulations, the atoms in the QM and MM Parts are dynamically adjusted. To examine the effects of local microenvironments on the chemical processes, atomic oxygen is used as a chemical probe to scan the gas-liquid interface. The excited atomic oxygen reacts with water molecules and Cl− ions to produce H2O2, OH, HOCl, ClO−, and HO2−/H3O+ species. The ground-state atomic oxygen is significantly more stable than the excited atomic oxygen, although it can react with water molecules to produce OH radicals. However, the branch ratio of ClO− computed for triplet atomic oxygen is significantly larger than that determined for singlet atomic oxygen. This study can help achieve a better understanding of the fundamental chemical processes during plasma-treated solution experiments and promotes advances in applications of QM/MM calculations at the gas-liquid interface.

Origins of Conformational Heterogeneity in Peptoid Helices Formed by Chiral N-1-Phenylethyl Sidechains.

N-substituted glycines (polypeptoids) containing chiral hydrophobic sidechains are known to fold into biomimetic alpha helices. These helix formers often produce conformationally heterogeneous structures and are difficult to characterize at a sub-nanometer resolution. Previously, peptoid N-1-phenylethyl (S)-enantiomer sidechains (Nspe) were inferred from various experiments to form right-handed helices and (R)-enantiomers (Nrpe), left-handed helices. Prior computational work for N(s/r)pe oligomers has struggled to reproduce this trend. Herein, quantum mechanics calculations and molecular dynamics simulations are used to understand the origins of this discrepancy. Results from DFT and molecular mechanics calculations on a variety of Nspe and Nrpe oligomers as a function of chain length are in agreement, showing that Nspe and Nrpe prefer left- and right-handed helices, respectively. Additional metadynamics simulations are used to study Nrpe and Nspe oligomers folding in water. These results show that the free-energy driving forces for assembly into a helical backbone configuration are very small (within ∼kBT). Lastly, we compare DFT calculations for other experimentally characterized peptoid sidechains, N(r/s)sb, N(r/s)tbe, and N(r/s)npe. In this analysis, we show that peptoid sidechains determined to be more robust experimentally (tbe and npe) have helical preferences opposite the trend seen in less robust assemblies formed by N(r/s)pe and N(r/s)sb chemistries. The more robust tbe and nnpe favor the (S)-enantiomer to right-handed and the (R)-enantiomers to left-handed helices.

Growth Mechanism and Kinetics of Diamond in Liquid Gallium from Quantum Mechanics Molecular Dynamics Simulations.

Ruoff and co-workers recently demonstrated low-temperature (1193 K) homoepitaxial diamond growth from liquid gallium solvent. To develop an atomistic mechanism for diamond growth underlying this remarkable demonstration, we carried out density functional theory-based molecular dynamics (DFT-MD) simulations to examine the mechanism of single-crystal diamond growth on various low-index crystallographic diamond surfaces (100), (110), and (111) in liquid Ga with CH4. We find that carbon linear chains form in liquid Ga and then react with the growing diamond surface, leading first to the formation of carbon rings on the surface and then initiation of diamond growth. Our simulations find faster growth on the (110) surface than on the (100) or (111) surfaces, suggesting the (110) surface as a plausible growth surface in liquid Ga. For (110) surface growth, we predict the optimum growth temperature to be ∼1300 K, arising from a balance between the kinetics of forming carbon chains dissolved in Ga and the stability of carbon rings on the growing surface. We find that the rate-determining step for diamond growth is dehydrogenation of the growing hydrogenated (110) surface of diamond. Inspired by the recent experimental studies by Ruoff and co-workers demonstrating that Si accelerates diamond growth in Ga, we show that addition of Si into liquid Ga significantly increases the rate of dehydrogenating the growing surface. Extrapolating from the DFT-MD predicted rates at 2800 to 3500 K, we predict the growth rate at the experimental growth temperature of 1193 K, leading to rates in reasonable agreement with the experiment. These fundamental mechanisms should provide guidance in optimizing low-temperature diamond growth.

Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations.

The initial phases of drug discovery - in silico drug design - could benefit from first principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines - so far an unmet and crucial goal - will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance. We also demonstrate for the first time strong scaling of MiMiC-QM/MM MD simulations with parallel efficiency of ∼70% up to >80,000 cores. Thus, among many others, the MiMiC interface represents a promising candidate toward exascale applications by combining machine learning with statistical mechanics based algorithms tailored for exascale supercomputers.

Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations.

Combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations were performed to investigate the catalytic mechanism of human T-cell leukemia virus type 1 (HTLV-1) protease, a retroviral aspartic protease that is a potential therapeutic target for curing HTLV-1-associated diseases. To elucidate the proteolytic cleavage mechanism, we determined the two-dimensional free energy surfaces of the HTLV-1 protease-catalyzed reactions through various possible pathways. The free energy simulations suggest that the catalytic reactions of the HTLV-1 protease occur in the following sequential steps: (1) a proton is transferred from the lytic water to Asp32', followed by the nucleophilic addition of the resulting hydroxyl to the carbonyl carbon of the scissile bond, forming a tetrahedral oxyanion intermediate, and (2) a proton is transferred from Asp32 to the peptide nitrogen of the scissile bond, leading to the spontaneous breakage of the scissile bond. The rate-limiting step of this catalytic process is the proton transfer from Asp32 to the peptide nitrogen of the scissile bond, with a free energy of activation of 21.1 kcal/mol. This free energy barrier is close to the experimentally determined free energy of activation (16.3 kcal/mol) calculated from the measured catalytic rate constant (kcat). This mechanistic study provides detailed dynamic and structural information that will facilitate the design of mechanism-based inhibitors for the treatment of HTLV-1-associated diseases.

Coupling of conformation and CPD damage in nucleosomal DNA

UV-light can cause photodimerization and hence damages in DNA. Most frequent are cyclobutane pyrimidine dimer (CPD) damages, which predominantly form at TpT (thymine-thymine) steps. It is well known that CPD damage probability is different for single-stranded or double stranded DNA and depends on the sequence context. However, DNA deformation due to packing in nucleosomes can also influence CPD formation. Quantum mechanical calculations and Molecular Dynamics simulations indicate little CPD damage probability for DNA's equilibrium structure. We find that DNA needs to be deformed in a specific way to allow the HOMO → LUMO transition required for CPD damage formation. The simulation studies further show that the periodic CPD damage patterns measured in chromosomes and nucleosomes can be directly explained by the periodic deformation pattern of the DNA in the nucleosome complex. It supports previous findings on characteristic deformation patterns found in experimental nucleosome structures that relate to CPD damage formation. The result may have important implications for our understanding of UV-induced DNA mutations in human cancers.

Deciphering Structural and Dynamical Properties of Hydrated Cobalt Porphyrins via Ab Initio Quantum Mechanical Charge Field Molecular Dynamics Simulation.

The present study successfully implemented the ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism for the investigation of structural and dynamical properties of hydrated cobalt-porphyrin complexes. Considering the significance of cobalt ions in biological systems (for instance, vitamin B12), which reportedly incorporate cobalt ions in a d6, low spin, +3 state chelated in the corrin ring, an analog of porphyrin, the current study is focused on cobalt in the oxidation states +2 and +3 bound to the parent porphyrin lead structures embedded in an aqueous solution. These cobalt-porphyrin complexes were investigated in terms of their structural and dynamical properties at the quantum chemical level. The structural attributes of these hydrated complexes revealed the contrasting features of the water binding to these solutes, including a detailed evaluation of the associated dynamics. The study also yielded notable findings in regard to the respective electronic configurations vs coordination, which suggested that Co(II)-POR possesses a 5-fold square pyramidal coordination geometry in an aqueous solution containing the metal ion coordinating to four nitrogen atoms of the porphyrin ring and one axial water as the fifth ligand. On the other hand, high-spin Co(III)-POR was hypothesized to be more stable due to the smaller size-to-charge ratio of the cobalt ion, but the high-spin complex demonstrated unstable structural and dynamical behavior. However, the corresponding properties of the hydrated Co(III)LS-POR revealed a stable structure in an aqueous solution, thus suggesting the Co(III) ion to be in a low-spin state when bound to the porphyrin ring. Moreover, the structural and dynamical data were augmented by computing the free energy of water binding to the cobalt ions and the solvent-accessible surface area, which provide further information on thermochemical properties of the metal-water interaction and the hydrogen bonding potential of the porphyrin ring in these hydrated systems.

Exploring hydration mechanism of salt ions on the methane hydrate formation: Insights from experiments, QM calculations and MD simulations

A fundamental understanding of the hydration mechanism of salt ions on the methane hydrate formation would be beneficial for the interpretation of the reservoir formation mechanism and the development and utilization of natural gas hydrate. In this work, the hydration of salt ions (Na+ and Cl-) on the methane hydrate formation is investigated using experiments, quantum mechanics (QM) calculations and molecular dynamics (MD) simulations. The results show the salts ions firstly influence the orientation of the H2O molecules and then influence the OH symmetrical stretching vibrations by impacting the tetrahedral arrangement of H2O molecules after attaching the hydration-shell layers. The coupling process of the hydration and the mass transfer of salt ions influence the methane hydrate formation.

Computational study of inclusion complexes of V-type nerve agents (VE, VG, VM, VR and VX) with β-cyclodextrin

The effective detoxification of organophosphate (OP) nerve agents (OPNAs) is a challenging issue for scientists. The host–guest inclusion complexes of five V-type nerve agents (VE, VG, VM, VR and VX) with β-cyclodextrin (β-CD) have been studied by combining quantum mechanical (QM) calculations and molecular dynamics (MD) simulations. The frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) have been analyzed to describe the reactivity parameters and electronic properties. The obtained results clearly reveal that stable complexes were formed in both vacuum and water media, and the complexation process occurred spontaneously. To understand non-covalent interactions, natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) have been used. IR and Raman spectra have been calculated to confirm the formation of complexes and also thermodynamic parameters have been investigated. It was demonstrated that in addition to van der Waals interactions, the presence of intermolecular hydrogen bonds enhances the stability of these complexes. Furthermore, MD simulations were carried out to get a better insight into the inclusion process of the above complexes. From MD simulations, all simulated systems reached full equilibration at 1000 ps and the V-agent molecules consistently remained in the β-CD cavity and only had vibrational motion inside the cavity. More importantly, MD simulations support the findings of QM calculations and indicate that hydrogen bonding can help the leaving groups of V-agents to be released and them to be hydrolyzed. All results have shown that the VR agent formed the most stable complex with β-CD molecule than that of other agents. Communicated by Ramaswamy H. Sarma

Amino-Acid Based Chiral Trisubstituted Benzimidazole Supramolecules: Synthesis and Self-Assembling Behavior.

Trisubstituted 1,3,5-tri(benzimidazolyl)benzene derivatives were synthesized from l-alanine, l-valine, d-valine and glycine, and their self-assembling behavior and stimuli-response in solution and gel states were evaluated. Circular dichroism/UV-vis absorption spectroscopic and dynamic light scattering measurements revealed that the compounds formed H-aggregates via intramolecular hydrogen bonding and π-π stacking interactions in nonpolar solvents such as CHCl3, whereas collapse of the aggregates was confirmed by MeOH addition. Quantum mechanical calculations and molecular dynamics simulations also supported aggregation in CHCl3 . Rheological analysis and morphology observation revealed the formation of a fibril like structure by further assembling of aggregates at a high concentration in CHCl3 .

Physisorption of biodegradable choline-based ionic liquids (CBILs) and their aqueous solutions on 2D titanium carbide (MXene) nanosheets as promising media in energy storage systems

MXenes alongside ionic liquid electrolytes have been promising in energy storage systems. The nanoscopic structure of two biodegradable choline-based ionic liquids (CBILs) and their water mixtures were investigated near the MXene surface using quantum mechanics calculations and molecular dynamics simulations. Quantum mechanics calculations showed that the anion-cation interactions in the choline salicylate ([CH][SA]) are weaker than that for choline β-alaninate ([CH][β-Ala]), therefore, [SA]− tends to interact more with the MXene surface compared to [β-Ala]−. Simulation results indicated that the ionic liquids aggregate in the vicinity of the MXene surface to form a dense layer with significantly different properties compared to bulk. Applying moisture to CBIL systems reduces the ion population in the first layer and also their structural correlations. Furthermore, there is a competition between water molecules and choline cations for interaction with anions. The presence of water molecules also increases the dynamics of hydrogen bonds, ion pairs, and ion cages. Perception of the nano-scale behavior of these unique classes of ionic liquids on MXenes could be beneficial for energy storage systems like batteries and electric double-layer capacitors.

Water Charge Transfer Accelerates Criegee Intermediate Reaction with H2O- Radical Anion at the Aqueous Interface.

Criegee intermediates (CIs) are important carbonyl oxides that may react with atmospheric trace chemicals and impact the global climate. The CI reaction with water has been widely studied and is a main channel for trapping CIs in the troposphere. Previous experimental and computational reports have largely focused on reaction kinetic processes in various CI-water reactions. The molecular-level origin of CI's interfacial reactivity at the water microdroplet surface (e.g., as found in aerosols and clouds) is unclear. In this study, by employing the quantum mechanical/molecular mechanical (QM/MM) Born-Oppenheimer molecular dynamics with the local second-order Møller-Plesset perturbation theory, our computational results reveal a substantial water charge transfer up to ∼20% per water, which creates the surface H2O+/H2O- radical pairs to enhance the CH2OO and anti-CH3CHOO reactivity with water: the resulting strong CI-H2O- electrostatic attraction at the microdroplet surface facilitates the nucleophilic attack to the CI carbonyl by water, which may counteract the apolar hindrance of the substituent to accelerate the CI-water reaction. Our statistical analysis of the molecular dynamics trajectories further resolves a relatively long-lived bound CI(H2O-) intermediate state at the air/water interface, which has not been observed in gaseous CI reactions. This work provides insights into what may alter the oxidizing power of the troposphere by the next larger CIs than simple CH2OO and implicates a new perspective on the role of interfacial water charge transfer in accelerating molecular reactions at aqueous interfaces.

Coating of favipiravir (FVP) on silver nanoparticles: First principle study

Silver nanoparticles, thanks to their antiviral and antibacterial properties, have great potential in a variety of applications, such as drug-delivery carriers. The coating properties of silver nanoparticles (size range of 1.6 nm) with a well-known drug, Favipirair, were investigated in this study using quantum mechanical and classical atomistic molecular dynamics simulation in order to use as the drug delivery to treat COVID-19 disease. The drug molecule's optimized structure, frequencies, charge distribution, and electrostatic potential maps were simulated using density functional theory (DFT) at the B3LYP/6–311++g(d,p) level of theory. The coating of AgNP with each of these drugs was then studied using molecular dynamics simulation. The interaction affinity obtained from MD results agrees with the DFT results on drug adsorption on the Ag(111) slab.

Tautomer-Specific Deacylation and Ω-Loop Flexibility Explain the Carbapenem-Hydrolyzing Broad-Spectrum Activity of the KPC-2 β-Lactamase.

KPC-2 (Klebsiella pneumoniae carbapenemase-2) is a globally disseminated serine-β-lactamase (SBL) responsible for extensive β-lactam antibiotic resistance in Gram-negative pathogens. SBLs inactivate β-lactams via a mechanism involving a hydrolytically labile covalent acyl-enzyme intermediate. Carbapenems, the most potent β-lactams, evade the activity of many SBLs by forming long-lived inhibitory acyl-enzymes; however, carbapenemases such as KPC-2 efficiently deacylate carbapenem acyl-enzymes. We present high-resolution (1.25-1.4 Å) crystal structures of KPC-2 acyl-enzymes with representative penicillins (ampicillin), cephalosporins (cefalothin), and carbapenems (imipenem, meropenem, and ertapenem) obtained utilizing an isosteric deacylation-deficient mutant (E166Q). The mobility of the Ω-loop (residues 165-170) negatively correlates with antibiotic turnover rates (kcat), highlighting the role of this region in positioning catalytic residues for efficient hydrolysis of different β-lactams. Carbapenem-derived acyl-enzyme structures reveal the predominance of the Δ1-(2R) imine rather than the Δ2 enamine tautomer. Quantum mechanics/molecular mechanics molecular dynamics simulations of KPC-2:meropenem acyl-enzyme deacylation used an adaptive string method to differentiate the reactivity of the two isomers. These identify the Δ1-(2R) isomer as having a significantly (7 kcal/mol) higher barrier than the Δ2 tautomer for the (rate-determining) formation of the tetrahedral deacylation intermediate. Deacylation is therefore likely to proceed predominantly from the Δ2, rather than the Δ1-(2R) acyl-enzyme, facilitated by tautomer-specific differences in hydrogen-bonding networks involving the carbapenem C-3 carboxylate and the deacylating water and stabilization by protonated N-4, accumulating a negative charge on the Δ2 enamine-derived oxyanion. Taken together, our data show how the flexible Ω-loop helps confer broad-spectrum activity upon KPC-2, while carbapenemase activity stems from efficient deacylation of the Δ2-enamine acyl-enzyme tautomer.

Unraveling Binding Mechanism and Stability of Urease Inhibitors: A QM/MM MD Study

Soil bacteria can produce urease, which catalyzes the hydrolysis of urea to ammonia (NH3) and carbamate. A variety of urease inhibitors have been proposed to reduce NH3 volatilization by interfering with the urease activity. We report a quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) study on the mechanism employed for the inhibition of urease by three representative competitive inhibitors; namely, acetohydroxamic acid (AHA), hydroxyurea (HU), and N-(n-butyl)phosphorictriamide (NBPTO). The possible connections between the structural and thermodynamical properties and the experimentally observed inhibition efficiency were evaluated and characterized. We demonstrate that the binding affinity decreases in the order NBPTO >> AHA > HU in terms of the computed activation and reaction free energies. This trend also indicates that NBPTO shows the highest inhibitory activity and the lowest IC50 value of 2.1 nM, followed by AHA (42 μM) and HU (100 μM). It was also found that the X=O moiety (X = carbon or phosphorous) plays a crucial role in the inhibitor binding process. These findings not only elucidate why the potent urease inhibitors are effective but also have implications for the design of new inhibitors.

Effect of silver nanoparticle size on interaction with artemisinin: First principle study

According to their antiviral and antibacterial capabilities, silver nanoparticles hold great promise in a wide variety of applications, including drug delivery carriers. The coating properties of silver nanoparticles (various sizes ranging from 1 to 5 nm) with the most commonly used anti-malarial drug, artemisinin, were investigated in this study using quantum mechanical and classical atomistic molecular dynamics simulations in order to determine their suitability for use as drug delivery in the treatment of malaria and COVID-19 diseases. Density functional theory (DFT) at the B3LYP/6-311++g(d,p) level of theory was used to simulate the optimal structure, frequency, charge distribution, and electrostatic potential maps of artemisinin. The adsorption of drugs on the Ag nanoparticle (55 silver atoms) was investigated using DFT simulations. Then, using molecular dynamics simulations, the coating of AgNPs (various sizes) with drug molecules was investigated. The influence of AgNPs’ size and composition on the coating with artemisinin was determined in order to identify the most suitable candidate for drug delivery. This type of modeling may aid experimental groups in developing effective and safe therapies.

Combined quantum mechanics and molecular dynamics study on the calcite scale inhibition mechanism of carboxymethyl dextran

The scale inhibition mechanism of carboxymethyl dextran (CMD), a new green scale inhibitor, was studied via quantum mechanical calculations and molecular dynamics (MD) simulations. Specifically, the interactions between the functional groups of CMD and calcite (104), (110), and (1–10) surfaces in aqueous solution were modelled at different degrees of polymerization (DP) of CMD (2, 4, 6, 8, and 10, respectively). The adsorption configuration, radial distribution function, deformation energy, binding energy, and relative concentration distribution of water molecules near the surface of calcite were calculated. The results showed that the carboxyl functional groups in CMD were strongly electronegative and able to form strong chemisorption bonds with calcium ions on the calcite surface. This can change the regular arrangement of the surface and prevent the combination of carbonate particles and calcium ions to form calcite scale. Furthermore, as the DP increased, the binding energy and the peak value of the radial distribution function increased, indicating an increase in the probability and strength of adsorption of CMD on the calcite surface, which can further enhance the scale inhibition efficiency.

An Efficient Multilayer Approach to Model DNA-Based Nanobiosensors.

In this work, we present a full computational protocol to successfully obtain the one-electron reduction potential of nanobiosensors based on a self-assembled monolayer of DNA nucleobases linked to a gold substrate. The model is able to account for conformational sampling and environmental effects at a quantum mechanical (QM) level efficiently, by combining molecular mechanics (MM) molecular dynamics and multilayer QM/MM/continuum calculations within the framework of Marcus theory. The theoretical model shows that a guanine-based biosensor is more prone to be oxidized than the isolated nucleobase in water due to the electrostatic interactions between the assembled guanine molecules. In addition, the redox properties of the biosensor can be tuned by modifying the nature of the linker that anchor the nucleobases to the metal support.

Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY

Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY’s coumarin synthase activity. Our structural analyses reveal an unconventional active-site configuration adapted to COSY’s specialized activity. Through mutagenesis studies and deuterium exchange experiments, we identify a unique proton exchange mechanism at the α-carbon of the o-hydroxylated trans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Quantum mechanical cluster modeling and molecular dynamics further support this key mechanism for lowering the activation energy of the rate-limiting trans-to-cis isomerization step in coumarin production. This study unveils an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on COSY’s evolutionary origin and its recruitment to coumarin biosynthesis in eudicots.