Journal of Molecular Modeling最新文献

Context

Copper is an essential trace element that plays a central role in redox chemistry and electron transfer processes in biological systems. To gain a deeper understanding of the electronic behavior of copper species, we carried out a comparative evaluation of the Cu₂ and CuO molecules, focusing on key properties such as ionization energy, electron affinity, vibrational frequencies, bond lengths, and dissociation energies. Cu₂ serves as a model for dinuclear copper sites present in metalloproteins like tyrosinase and hemocyanin, while CuO captures the essential features of copper-oxygen bonding relevant to copper-dependent oxidases and oxygen-activating enzymes. By systematically benchmarking density functional approximations (DFAs) against high-level CCSD(T) reference calculations or experimental data, we identify the methodologies that best reproduce the electronic and structural properties of these prototypical copper systems. The functional PBE, in particular, demonstrates the most consistent performance across both species. Insights obtained from Cu₂ and CuO serve as a foundation for understanding more complex copper coordination environments. In this context, we extend our analysis to the Cu(II)/indomethacin complex, illustrating how the lessons learned from the fundamental systems can be applied to biologically relevant copper-ligand interactions. Overall, this study provides a systematic assessment of the accuracy of different DFAs for describing copper-containing species, establishing a solid framework for future investigations of bioinorganic copper chemistry and copper-based drug candidates.

Methods

This study employed density functional theory (DFT) alongside thermodynamic cycles to assess the stability of Cu(Indo)₂ and Cu₂(Indo)₄ complexes in ethanol solution. To select suitable computational methods, a benchmark was conducted using Cu(II)/acetate complexes as reference systems. A total of fifteen DFT functionals—BPW91, PBE, B97D, revTPSS, M06-L, M11-L, B3LYP, BHandHLYP, PBE0, ωB97XD, APDF, M06, M06-2X, M06-HF, and TPSSh—were tested in combination with four basis sets: Def2-SVP, Def2-TZVP, 6–31 + G(d,p), and 6–311 + G(d,p). The most reliable functional-basis set combinations were then applied to the copper-indomethacin complexes. In addition, electronic and structural properties of Cu₂ and CuO—such as ionization potentials, electron affinities, vibrational frequencies, equilibrium bond lengths, and spin or magnetic coupling constants—were calculated. Computational results were validated through comparison with available experimental data.

Context

The main protease (M^pro) of SARS-CoV-2 is highly conserved with low variability. It plays a key role in viral replication, making it a target for COVID-19 treatment. Currently, drugs like Paxlovid have significant side effects and high costs, so new alternatives are urgently needed.

Methods

In this work, a medicine and food homology herbal drugs (MF-HHD) database is constructed, followed by a multi-scale and high-precision screening with various virtual screening techniques (ligand-based pharmacophore screening, Vina-based screening, and drug-forming, prescription-based screening). Quercetin was identified as a potent M^pro inhibitor through multi-stage virtual screening. Molecular dynamics simulations (500 ns) revealed its binding mechanism and stabilization effects on M^pro. The results revealed that upon binding, the inhibitor interacted with H41, H164, M165, L167, P168, D187, R188, Q189, and Q192 and altered the hydrogen bonding network between M^pro and the solvent allowing the inhibitor to bind the active pocket. Free energy landscape (FEL) and conformational clustering analysis showed that M^pro undergoes significant conformational changes when bound to quercetin. In this way, a complete drug screening chain will be used to search for potential M^pro inhibitors and obtain computationally validated candidate that can for experimental evaluation COVID-19.

Context

Two allomorphic crystals, photochromic N-salicylidene-4-bromoaniline (α-SA4B) and non-photochromic N-salicylidene-4-chloroaniline (β-SA4C), were simulated using a hierarchical hybrid quantum mechanical (QM/QM′) method. Despite the similar potential energy surface (PES) profiles observed in their isolated forms, distinct differences emerged in the cluster model simulations of α-SA4B and β-SA4C. This observation suggests that the molecular environment influenced the torsional energy landscape associated with their chromic properties.

Method

Each crystal was represented by a cluster model consisting of a central molecule and 14 peripheral molecules arranged based on crystallographic symmetry. The central molecule was treated as the high-level QM layer, while the surrounding molecules were kept fixed as the low-level QM′ layer. Following iterative optimization of the cluster model, the PES was calculated to track the cis-trans isomerization process of the central molecule. The iterative optimization was conducted with ONIOM (B3LYP/6-311G**: HF-D3BJ/6-31G*), and the PES was calculated with the same level. For each cluster model, the excited state was calculated with the TD-DFT method. All the quantum chemical calculations were performed using Gaussian 16 software.

Graphical abstract

Context

The furazan-based energetic material 3,4-bis(3-nitrofuazan-4-yl)furoxan (DNTF) is widely utilized in mixed explosives such as melt-cast explosives, high-power warheads, and propellants. The high-pressure response of DNTF exhibits unresolved uncertainties requiring further investigation. Therefore, in this paper, we focus on the structural stability of DNTF under high pressure. The structural, electronic, and mechanical properties and sensitivity characteristics under 0–100 GPa have been integrally studied. At ambient pressure, the phonon spectrum and mechanical properties confirm structural stability. Under compression, the crystal exhibits pronounced anisotropy. Applied pressure induces pronounced anisotropy in the crystal structure. A pressure-driven transition from van der Waals interactions to covalent bonds occurs at 80 GPa. Electronic analysis reveals bandgap reduction and effective mass decrease under compression corresponding to enhanced impact sensitivity. Mechanical property evaluations verify dynamic stability across the studied pressure range. Calculated B/G ratios and Cauchy pressure (({C}_{12}-{C}_{44})) values demonstrate ductile behavior of DNTF under these pressures. These integrated findings deepen understanding of DNTF’s high-pressure structural evolution and mechanical responses providing crucial theoretical foundations for material design and safety assessments under extreme pressures.

Methods

Density functional theory calculations were performed to investigate the structural, electronic, and mechanical properties of the furazan-based energetic material 3,4-bis(3-nitrofuazan-4-yl)furoxan (DNTF) under 0–100-GPa pressures. The calculations were performed in the CASTEP code using the norm-conserving pseudopotential approach.

Context

Intrinsic, oriented electric fields inside protein active sites, quantified by vibrational Stark effect (VSE) measurements and electrostatic calculations have been implicated in catalytic preorganization, yet their systematic use to program drug–target lifetimes has remained underexplored. We advance a field-first paradigm in which the component of the protein field projected along a dominant reaction coordinate, denoted as ({E}_{parallel }) (the component of the protein’s electric field along the reaction coordinate), serves as a tunable design variable for off-rate and residence time (τ). Focusing on two mechanistic archetypes proton sharing (Ketosteroid Isomerase, KSI-like) and bond polarization/dissociation (human aldose reductase, hALR2-like) we show that realistic changes in ({E}_{parallel }) can tilt barriers, alter curvatures, and modulate tunneling, yielding exponential leverage on kinetics. This reframes pharmacodynamic lifetime as an electrostatic, geometry-addressable property, complementary to affinity optimization and accessible through protein mutations or ligand substituents that re-orient local dipoles.

Method

We developed a predictive, quantum–mechanical framework grounded in analytical solutions to the one-dimensional time-independent Schrödinger equation. Two experimentally validated systems were modeled viz the proton-transfer dynamics in ketosteroid isomerase (KSI) using an asymmetric double-well potential, and carbonyl polarization/dissociation in human aldose reductase (hALR2) using a modified Morse potential. The intrinsic Stark field was incorporated via its projection onto the reaction coordinate (({E}_{parallel })), coupling through molecular dipole and polarizability terms to tilt and reshape the potential energy landscape. The resulting eigenvalues and wavefunctions provided the parameters for a Grote-Hynes-corrected transition-state theory model with explicit quantum tunneling corrections. This approach quantitatively connects field strength to activation barriers, vibrational frequencies, and ultimately the off-rate (({k}_{off})), enabling the prediction of how perturbations via mutagenesis or ligand design alter residence time.

Context

Recently, newly developed organic ferroelectric materials have garnered significant interest due to their suitability for electronic applications. Among these materials, diisopropylammonium bromide (dipaBr) stands out for its remarkable properties, exhibiting a spontaneous polarization of 23 μC/cm² and a high Curie temperature of 425 K, making it a promising candidate for practical applications. In this investigation, the nonlinear optical behavior of pristine and halogen-substituted diisopropylammonium bromide crystals was explored using density functional theory, aiming to elucidate the influence of chemical doping on the material’s optical characteristics. The unmodified dipaBr structure was initially geometrically optimized, followed by a systematic replacement of the bromide anion with halogen atoms fluorine (F), chlorine (Cl), and iodine (I) to examine the resulting alterations in electronic configuration, molecular polarizability, and first hyperpolarizability (β), which are pivotal descriptors of second-order NLO effects. The computed NLO parameters reveal that the dipole moments for pristine and halogen-doped dipaBr are 18.96 D, 17.50 D, 10.18 D, and 11.41 D, respectively, as derived from the LANL2DZ basis set using CAM-B3LYP functional.

Methods

The nonlinear optical properties of pristine diisopropylammonium bromide (dipaBr) and its halogen-doped derivatives were investigated using Density Functional Theory (DFT). The computations were carried out using the B3LYP functional with the 6–31 + G(d), 6–311 +  + G(d,p), and LANL2DZ basis sets, together with the CAM-B3LYP functional employing the 6–311 +  + G(d,p) and LANL2DZ basis sets. The computational outputs were visualized using Gauss View 6 software. Halogen incorporation led to notable modifications in the electronic band gap and charge density distribution, with a marked increase in dipole moment and β values, particularly for the F- and I-substituted systems. Furthermore, the thermodynamic parameters of pristine and halogen-doped diisopropylammonium bromide are systematically analyzed.

Context

The unique combination of fluidity like liquids and directional organization like solids in liquid crystals (LCs) gives rise to their special properties. This article presents a theoretical study on Schiff’s base thermotropic LC, tetraphthalylidene-bis-p-n-alkylaniline (TBnA) homologous series (n = 4–8). The aim is to understand the relationship between the molecular design and physical properties with varying alkyl chain length. Optimized molecular geometries, electronic, thermodynamic, and nonlinear optical (NLO) parameters are calculated theoretically. The polarizability of the LCs is high, and the first-order hyperpolarizability is not zero, which makes them a good candidate for NLO applications. A consistent 3.55 eV energy gap across a series indicates a uniform electronic structure, positioning them as promising candidates for optoelectronics applications, and chemically stable and tunable wide band gap requiring fields. UV–Vis absorption spectra calculated using TD-DFT explored oscillator strength and involved electronic transitions. Raman and IR modes aid in characterizing functional groups and phase transition markers. The results reveal valuable insights into the electronic distribution, stability, and excitation of TBnA, providing a theoretical foundation for the design and optimization of LCs for advanced optoelectronic applications.

Methods

The widely accepted DFT with B3LYP functional is used for the simulation along with 6-311G(d,p) basis set in Gaussian 09 software. All the frontier orbitals, thermodynamic, NLO, and spectroscopic studies are performed at the same computational level. Time-dependent DFT (TDDFT) and the multiwfn software are used for the UV–Vis spectra. Vibrational spectroscopy assignment analyses are done using VEDA software and GaussView animation.

Context

The modulation of autophagy – inhibition or induction – has emerged as a promising strategy in cancer treatment, offering significant advantages over conventional chemotherapy. Previously, we demonstrated that the vanadium complex [VO(oda)(phen)] inhibits autophagy by activating the phosphoinositide 3-kinase gamma (PI3Kγ) protein. Given the therapeutic potential of autophagy modulation, we proposed structural modifications to this complex to achieve the opposite effect: autophagy activation by preventing PI3Kγ activation. In this context, this study aimed to perform structural modifications on the vanadium complex to elucidate and discuss new conformational implications and its role in the autophagic machinery. The AMBER force field (FF) was adapted for the modified vanadium complex (mVC), yielding excellent results in molecular dynamics (MD) simulations in vacuum, protein, and aqueous environments. The structural modifications successfully disrupted the interaction between [VO(oda)(phen)] and PI3Kγ, previously identified as a key factor in PI3Kγ activation. Consequently, PI3Kγ deactivation leads to a shift in the autophagy signaling pathway, promoting autophagy activation. Additionally, NMR calculations were performed to explore a novel role for mVC, broadening its potential applications.

Methods

MD simulations were conducted at 800 ns using the AMBER program, while Molegro Virtual Docker (MVD) was employed for docking simulations. Optimization calculations (B3LYP/def2-TZVP and LANL2DZ ECP for V) and NMR calculations (PBE/IGLO-II and Wachters + f for V) were performed using Gaussian 09. The key frames from the MD simulations were selected using the OWSCA algorithm. Ligand and protein performance were evaluated through RMSD, RMSF, and hydrogen bond analyses, applying cutoff distances of 3.5 Å and 30°.

Context

The accurate prediction of the standard enthalpy of formation (ΔHf°) is crucial for understanding molecular stability and reaction energetics, yet reliable experimental data are often unavailable for unstable or novel compounds. This work benchmarks three Minnesota density functionals (M06-2X, MN12-SX, and MN15) to evaluate their performance in predicting ΔHf° values for a diverse set of hydrocarbons via the atom equivalent method. Our results identify MN15 as the most accurate functional, particularly when zero-point energy (ZPE) corrections are included, achieving a mean absolute error of 1.70 kcal/mol. In contrast, MN12-SX exhibits significant sensitivity to ZPE corrections, limiting its reliability. To enhance predictive robustness, a machine learning model was developed, which demonstrated strong performance on acyclic systems but highlighted challenges in predicting strained cyclic molecules. This hybrid quantum-chemical and data-driven framework provides a validated pathway for improving the accuracy of thermochemical predictions.

Methods

All quantum chemical calculations were performed using the Gaussian 16 software package. The density functionals M06-2X, MN12-SX, and MN15 were employed in conjunction with the correlation-consistent polarized valence triple-zeta (cc-pVTZ) basis set. Single-point electronic energies and vibrational frequencies for ZPE corrections were computed at the same level of theory. Enthalpies of formation were derived using the atom equivalent method, where carbon and hydrogen energy equivalents were obtained via least-squares fitting to experimental data. Also, a machine learning workflow was implemented in Python using the scikit-learn library, wherein a random forest regressor was trained on molecular descriptors and experimental ΔHf° values, with model performance assessed via fivefold cross-validation.

Graphical Abstract

Context

The development of ordered structures upon immediately quenching from 473 K to different crystallization temperatures (Tc = 300 K, 320 K, 340 K, and 360 K) of three n-alkanes (n-eicosane (C₂₀H₄₂), n-tetracontane (C₄₀H₈₂) and n-octacontane (C₈₀H₁₆₂) to accommodate the formation of bilayer, monolayer and the folded-chain configurations, respectively), was quantitatively analyzed by evaluating chain/bond order parameters, interaction energies, conformational statistics, local dynamics, structural pair correlation function, and X-ray scattering profiles. The formation of ordered structures seems to be best at Tc = 340 K. Generally, systems that tend to form the monolayer and folded-chain configurations exhibit the most and the least ordered structures, respectively. Chains in monolayer structures tend to have a larger fraction of trans state, higher anisotropy of bond orientation, slower monomer dynamics, and more densely packed structures than chains in bilayer structures, while longer alkanes with chain-folded structures exhibit the least characteristics of these properties. The nucleation temperature (Tn) can be affected by their structural configuration, with the highest Tn for the monolayer structure. Nevertheless, the melting temperature (Tm) tends to depend solely on the molecular weights of these alkanes, not on their structural configuration.

Methods

Monte Carlo (MC) simulation of the coarse-grained (CG) models of three n-alkanes (one CG bead equivalent to an ethylene unit) on the second nearest neighbor diamond (2nnd) lattice with the same periodic box dimension of 5 nm in each size. The energetics of CG models were composed of the Rotational Isomeric State (RIS) model and the Lennard–Jones (LJ) potential energies to represent their intra- and intermolecular interactions, respectively. Structure developments within 100 million Monte Carlo steps (MCS) trajectories were monitored, and data analysis was based on snapshots collected at intervals of 10,000 MCS. All simulations and data analysis were performed using in-house FORTRAN codes with the g77 compiler.