Mechanism‐Driven Unlocking of the Activity of Strictosidine Synthase Toward N1‐Substituted Tryptamine

Molecular dynamics simulation and quantum mechanical calculations on α-d-N-acetylneuraminic acid

β-Lactamases are bacterial enzymes that act as a bacterial defense system against β-lactam antibiotics. β-Lactamase cleaves the β-lactam ring of the antibiotic by a two step mechanism involving acylation and deacylation steps. Although class C β-lactamases have been investigated extensively, the details of their mechanism of action are not well understood at the molecular level. In this study, we investigated the mechanism of the acylation step of class C β-lactamase using pKa calculations, molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. Serine64 (Ser64) is an active site residue that attacks the β-lactam ring. In this study, we considered three possible scenarios for activation of the nucleophile Ser64, where the activation base is (1) Tyrosine150 (Tyr150), (2) Lysine67 (Lys67), or (3) substrate. From the pKa calculation, we found that Tyr150 and Lys67 are likely to remain in their protonated states in the pre-covalent complex between the enzyme and substrate, although their role as activator would require them to be in the deprotonated state. It was found that the carboxylate group of the substrate remained close to Ser64 for most of the simulation. The energy barrier for hydrogen abstraction from Ser64 by the substrate was calculated quantum mechanically using a large truncated model of the enzyme active site and found to be close to the experimental energy barrier, which suggests that the substrate can initiate the acylation mechanism in class C β-lactamase.

In this work, the effect of adding a monocationic ionic liquid (MIL) on the properties of a dicationic ionic liquid (DIL) was investigated using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. The binary mixture of [C6(mim)2][NTf2]2 (DIL) and [P1EOE][NTf2] (MIL) was analyzed in terms of thermophysical, structural, and dynamical properties, along with density functional theory (DFT) and atoms-in-molecules (AIM) analyses. These properties were compared to those of the pure DIL system. Structural properties were examined using radial distribution functions (RDFs) and hydrogen-bonding networks, providing insights into ion arrangement, spatial heterogeneity, and interaction strength. RDF analysis revealed that increasing the MIL mole fraction enhances the local density of anions near the ring hydrogen atoms more significantly than the bulk density. Furthermore, the orientation of imidazolium rings suggests that MIL promotes π-π stacking interactions among [C6(mim)2]2+ cations. Notably, the system with xMIL = 0.50 exhibited the lowest structural heterogeneity among the investigated mixtures. Dynamical properties, including mean square displacement (MSD), ionic conductivity, and van Hove correlation functions, were also analyzed. The results indicate that adding MIL enhances microheterogeneity and reduces ion cage strength, thereby facilitating ion mobility and increasing ionic conductivity. QM calculations further demonstrate that adding MIL lowers ion interaction energies due to the formation of stronger hydrogen bonds in the mixture. Additionally, AIM analysis reveals that the presence of MIL increases electron density between the dication and anions.

Sooting tendencies of a series of nitrogen-containing hydrocarbons (NHCs) have been recently characterized experimentally using the yield sooting index (YSI) methodology. This work aims to identify soot-relevant reaction pathways for three selected C6H15N amines, namely, dipropylamine (DPA), diisopropylamine (DIPA), and 3,3-dimethylbutylamine (DMBA) using ReaxFF molecular dynamics (MD) simulations and quantum mechanical (QM) calculations and to interpret the experimentally observed trends. ReaxFF MD simulations are performed to determine the important intermediate species and radicals involved in the fuel decomposition and soot formation processes. QM calculations are employed to extensively search for chemical reactions involving these species and radicals based on the ReaxFF MD results and also to quantitatively characterize the potential energy surfaces. Specifically, ReaxFF simulations are carried out in the NVT ensemble at 1400, 1600, and 1800 K, where soot has been identified to form in the YSI experiment. These simulations account for the interactions among test fuel molecules and pre-existing radicals and intermediate species generated from rich methane combustion, using a recently proposed simulation framework. ReaxFF simulations predict that the reactivity of the amines decrease in the order DIPA > DPA > DMBA, independent of temperature. Both QM calculations and ReaxFF simulations predict that C2H4, C3H6, and C4H8 are the main nonaromatic soot precursors formed during the decomposition of DPA, DIPA, and DMBA, respectively, and the associated reaction pathways are identified for each amine. Both theoretical methods predict that sooting tendency increases in the order DPA, DIPA, and DMBA, consistent with the experimentally measured trend in YSI. This work demonstrates that sooting tendencies and soot-relevant reaction pathways of fuels with unknown chemical kinetics can be identified efficiently through combined ReaxFF and QM simulations. Overall, predictions from ReaxFF simulations and QM calculations are consistent, in terms of fuel reactivity, major intermediates, and major nonaromatic soot precursors.

Molecular dynamics (MD) simulation and quantum mechanical (QM) calculations were used to investigate the reaction mechanism of sulbactam with class A wild-type SHV-1 β-lactamase including acylation, tautomerization, and deacylation. Five different sulbactam-enzyme configurations were investigated by MD simulations. In the acylation step, we found that Glu166 cannot activate Ser70 directly for attacking on the carbonyl carbon, and Lys73 would participate in the reaction acting as a relay. Additionally, we found that sulbactam carboxyl can also act as a general base. QM calculations were performed on the formation mechanism of linear intermediates. We suggest that both imine and trans-enamine intermediates can be obtained in the opening of a five-membered thiazolidine ring. By MD simulation, we found that imine intermediate can exist in two conformations, which can generate subsequent trans- and cis-enamine intermediates, respectively. The QM calculations revealed that trans-enamine intermediate is much more stable than other intermediates. The deacylation mechanism of three linear intermediates (imine, trans-enamine, cis-enamine) was investigated separately. It is remarkably noted that, in cis-enamine intermediate, Glu166 cannot activate water for attacking on the carbonyl carbon directly. This leads to a decreasing of the deacylation rate of cis-enamine. These findings will be potentially useful in the development of new inhibitors.

This work presents a systematic study of asphaltene pre-aggregation phenomena in the absence and in the presence of ionic liquids (ILs) from the family of 1-alkyl-3-methylimidazolium by molecular dynamics simulations. The effects of the alkyl chain length of the cation (studying ILs with alkyl chains between C4 and C10) and of the dimension of the anion (testing chloride and bromide) on the aggregation behavior of asphaltenes have been studied. To correlate the results obtained with the direct interaction between each additive and asphaltene, the latter was investigated both by the analysis of the radial distribution functions obtained by molecular dynamics simulations and quantum mechanical calculations. The DFT method was used to calculate the relative stability of the asphaltene-ionic liquid dimers and also the energy, shape, and spatial distribution of frontier orbitals. It was found that all the ionic liquids studied present a dispersing effect on asphaltene in model solvents, except for mixtures rich in toluene where, in most cases, the opposite effect is observed. This is accompanied by the interaction intensity as measured by radial distribution functions. The effects of the alkyl side chain length of the cation and of the anion radius are subtler, but it seems that the asphaltene dispersion effect increases with the length of the cation’s alkyl side chain and decreases with the radius of the anion; these effects are more clearly observed in the mixtures richer in n-heptane. These trends were corroborated by DFT calculations, which showed that the energetic stability of the asphaltene-additive dimer is as higher as the alkyl chain is longer and the anion is smaller. Pre-aggregation phenomena were also studied in mixtures containing CO2, which proved to be a precipitating agent as observed experimentally. The relative performances of the IL studied were not altered by the presence of CO2.

Molecular imprinting is a promising approach for developing polymeric materials as artificial receptors. However, only a few types of molecularly imprinted polymers (MIPs) are commercially available, and most research on MIPS is still in the experimental phase. The significant limitation has been a challenge for screening imprinting systems, particularly for weak functional target molecules. Herein, a combined method of quantum mechanics (QM) computations and molecular dynamics (MD) simulations was employed to screen an appropriate 2,4-dichlorophenoxyacetic acid (2,4-D) imprinting system. QM calculations were performed using the Gaussian 09 software. MD simulations were conducted using the Gromacs2018.8 software suite. The QM computation results were consistent with those of the MD simulations. In the MD simulations, a realistic model of the 'actual' pre-polymerisation mixture was obtained by introducing numerous components in the simulations to thoroughly investigate all non-covalent interactions during imprinting. This study systematically examined MIP systems using computer simulations and established a theoretical prediction model for the affinity and selectivity of MIPs. The combined method of QM computations and MD simulations provides a robust foundation for the rational design of MIPs.

The kinetic data published on phosphotriesterase (PTE), with various complexed metals, clearly indicates that the P=O and P=S bonds of phosphotriester and thiophosphotriester substrates, respectively, are strongly polarized by one or both of the active site complexed metal ions. However, this observation is not consistent with the three-dimensional X-ray crystal structure of zinc-substituted PTE with active site bound substrate analogue diethyl 4-methylbenzylphosphonate. In this structure, the distance between the phosphoryl oxygen and the nearest zinc is 3.4 A, a distance too large to afford strong polarization. In the present paper, the geometry and mobility of various PTE active site-substrate complexes are examined by performing both molecular dynamics (MD) simulations and quantum mechanical calculations. Two known substrates are considered, paraoxon and sarin, although their turnover rates vary about 100-fold. The results indicate that PTE forms a complex with either substrate in which the phosphoryl oxygen becomes strongly coordinated with the less buried zinc atom. It is shown that the geometry of the active site is changed when the protein is immersed in a water bath and relaxed by MD. The most substantial conformational change is the opening of the gateway in a pocket where the location of the leaving group is expected. The opening is observed for the pure enzyme as well as for the enzyme/substrate complexes and it ranges from 11 to 18 A. It is also shown that the pockets, in which the substrate substituents are localized, exhibit different flexibility and interact with the substrate with coordinated conformational adjustments.

Adsorption and encapsulation of the drug doxorubicin on covalent functionalized carbon nanotubes: A scrutinized study by using molecular dynamics simulation and quantum mechanics calculation

Structure and energetic properties of base pair mismatches in duplex RNA have been the focus of numerous investigations due to their role in many important biological functions. Such efforts have contributed to the development of models for secondary structure prediction of RNA, including the nearest-neighbor model. In RNA duplexes containing GU mismatches, 5'-GU-3' tandem mismatches have a different thermodynamic stability than 5'-UG-3' mismatches. In addition, 5'-GU-3' mismatches in some sequence contexts do not follow the nearest-neighbor model for stability. To characterize the underlying atomic forces that determine the structural and thermodynamic properties of GU tandem mismatches, molecular dynamics (MD) simulations were performed on a series of 5'-GU-3' and 5'-UG-3' duplexes in different sequence contexts. Overall, the MD-derived structural models agree well with experimental data, including local deviations in base step helicoidal parameters in the region of the GU mismatches and the model where duplex stability is associated with the pattern of GU hydrogen bonding. Further analysis of the simulations, validated by data from quantum mechanical calculations, suggests that the experimentally observed differences in thermodynamic stability are dominated by GG interstrand followed by GU intrastrand base stacking interactions that dictate the one versus two hydrogen bonding scenarios for the GU pairs. In addition, the inability of 5'-GU-3' mismatches in different sequence contexts to all fit into the nearest-neighbor model is indicated to be associated with interactions of the central four base pairs with the surrounding base pairs. The results emphasize the role of GG and GU stacking interactions on the structure and thermodynamics of GU mismatches in RNA.

Indium tri(isopropoxide)-catalyzed Meerwein-Ponndorf-Verley reduction of aliphatic and aromatic aldehydes in 2-propanol gave selectively the corresponding primary alcohols in good to excellent yields at room temperature. A wide range of functional groups including alkene, ether, ketone, ester, nitrile, and nitro were tolerated under the optimum reaction conditions. Chemoselective reductions were also achieved not only between aromatic aldehyde, aromatic ketone, and epoxide but also between aliphatic aldehyde and alkene.

Experimental and numerical study of the decomposition, product spectrum, and sooting properties of adamantane fuels

The treatment of tuberculosis (TB) has become challenging due to the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Consequently, new, and efficient therapies need to be developed to combat this dreaded disease. In this study, we apply in-silico techniques to analyse the potential inhibitory role of pyrazinone derivatives for enoyl-acyl carrier protein reductase (InhA), an important component protein involved in the synthesis of mycolic acids, the major components of the mycobacterial cell wall. Specifically, we amalgamated molecular docking, molecular dynamics (MD) simulations and quantum mechanical (QM) calculations to analyse the interaction of InhA with eight distinct pyrazinone derivatives, that contain thiophenyl, phenyl, or chloro substitutions at C6, ethyl or methoxybenzyl substitutions at N4, and carboxylate group (hydrolysed form of the parent carbonitrile group) at C2 position of the pyrazinone skeleton and compared our results with isoniazid, a well-known first-line TB drug that potentially inhibits InhA. Docking suggests that despite binding within the same pocket (albeit with different residues), pyrazinone derivatives interact more strongly with InhA than isoniazid. This points towards the potentially greater efficacy of these compounds than isoniazid towards InhA inhibition. Further, although C6 substitution does not significantly affect the ligand binding, N4-methoxybenzyl derivatives exhibit higher docking scores than their N4-ethyl counterparts, thereby suggesting their promising inhibitory potential against InhA. Extended (500 ns) all-atom explicit solvent MD simulations, amounting to a total of 9 µs of the simulation time, provide a refined picture of ligand binding in the explicit-solvent environment, and suggest that the crucial interaction with Arg 194 observed in the docked structures is mostly retained. Analysis of the hydrogen bond occupancies and binding-site linear interaction energies reiterate that the binding of the pyrazinone derivatives with InhA is stronger than isoniazid. In synchrony with MMGBSA binding energy calculations and QM calculations, these analyses reveal that irrespective of the nature of C6 substitution, pyrazinone derivatives with N4-methoxybenzyl substitution exhibit stronger binding to InhA, compared to those containing N4-ethyl substitution. Overall, this study identifies promising candidate compounds that should be experimentally tested for their potential inhibitory effects towards InhA.

Molecular dynamics and quantum mechanical calculations on the mononuclear zinc-β-lactamase from Bacillus cereus: Protonation state of the active site and imipenem binding

An electroreductive arylation reaction of aliphatic and aromatic aldehydes as well as ketones with electro-deficient (hetero)arenes is described. A variety of cyano(hetero)arenes and carbonyl compounds, especially aliphatic aldehydes, have been examined, providing secondary and tertiary alcohols in moderate to good yields. Mechanistic studies, including cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and divided-cell experiments, support the generation of aliphatic ketyl radicals and persistent heteroaryl radical anions via cathodic reduction followed by radical-radical cross-coupling.