Quantum Mechanical Force Field Research Articles

Exploring the Light-Emitting Agents in Renilla Luciferases by an Effective QM/MM Approach.

Bioluminescence is a fascinating natural phenomenon, wherein organisms produce light through specific biochemical reactions. Among these organisms, Renilla luciferase (RLuc) derived from the sea pansy Renilla reniformis is notable for its blue light emission and has potential applications in bioluminescent tagging. Our study focuses on RLuc8, a variant of RLuc with eight amino acid substitutions. Recent studies have shown that the luminescent emitter coelenteramide can adopt multiple protonation states, which may be influenced by nearby residues at the enzyme's active site, demonstrating a complex interplay between protein structure and bioluminescence. Herein, using the quantum mechanical consistent force field method and the semimacroscopic protein dipole-Langevin dipole method with linear response approximation, we show that the phenolate state of coelenteramide in RLuc8 is the primary light-emitting species in agreement with experimental results. Our calculations also suggest that the proton transfer (PT) from neutral coelenteramide to Asp162 plays a crucial role in the bioluminescence process. Additionally, we reproduced the observed emission maximum for the amide anion in RLuc8-D120A and the pyrazine anion in the presence of a Na+ counterion in RLuc8-D162A, suggesting that these are the primary emitters. Furthermore, our calculations on the neutral emitter in the engineered AncFT-D160A enzyme, structurally akin to RLuc8-D162A but with a considerably blue-shifted emission peak, aligned with the observed data, possibly explaining the variance in emission peaks. Overall, this study demonstrates an effective approach to investigate chromophores' bimolecular states while incorporating the PT process in emission spectra calculations, contributing valuable insights for future studies of PT in photoproteins.

Identification of cholesterol in different media by using the FT-IR, FT-Raman and UV–visible spectra combined with DFT calculations

In this investigation, the experimental FT-IR and FT-Raman spectra of cholesterol in the solid phase and in ethanol solution have been combined with the B3LYP/6–311++G** calculations and the scaled quantum mechanical force field (SQMFF) methodology, normal internal coordinates and transferable scaling factors to obtain the complete vibrational assignments of 216 vibration modes expected. Hence, complete vibrational assignments for that steroid of greatest biological importance are reported for first time in gas phase and ethanol solution together with its scaled force constants. Changes in the positions of some bands and in force constants values are observed in the different media due to the predicted intra-molecular interactions between CH3/CH3, CH3/CH2 and CH2/CH2 groups by atoms in molecules (AIM) calculations. The 1H- and 13C NMR chemical shifts of normal and deuterated cholesterol in aqueous solution confirm that the H atom of OH group is involved in the formation of H bonds in solution. Studies of experimental electronic spectra of cholesterol in different concentrations of ethanol revealed that the positions of peaks maxima increase conform increase the solution concentration. The natural bond orbital (NBO) analyses reveal that the polar OH group and the four fused rings play important roles in the stability and properties of cholesterol than the large hydrophobic moiety. Frontier orbitals predicted low reactivity of cholesterol in ethanol probably due to its high ω value in this medium.

Biomolecular dynamics with machine-learned quantum-mechanical force fields trained on diverse chemical fragments.

The GEMS method enables molecular dynamics simulations of large heterogeneous systems at ab initio quality.

Pyridazine derivative as potent antihyperglycemic agent: Synthesis, crystal structure, α-amylase and α-glucosidase inhibition and computational studies

In this study, a pyridazine derivative (PDZ-1) was synthesized and characterized by using 13C NMR, 1H NMR, FT-IR, UV–Vis, HRMS-ESI and single-crystal X-ray diffraction analysis (XRD). Density functional theory methods at the B3LYP/6–311++G** level of theory predict very good correlations in the geometrical parameters and spectra when they are compared with the corresponding experimental ones. The presence of dimer explains the broad IR band due to CH···O interactions. The scaled force constants and the 75 vibration modes of PDZ-1 have been completely assigned using the scaled quantum mechanical force field (SQMFF) methodology. The deactivating character of Cl atom probably explains that the densities of pyridazine rings in both media are higher than that corresponding to chlorobenzyl, as revealed by AIM study while NBO calculations show that the derivative is most stable in gas phase than ethanol solution. Frontier orbital studies reveal that PDZ-1 is most reactive in ethanol than in the gas phase. The title compound showed a potent α-glucosidase and α-amylase inhibition compared to Acarbose (IC50 = 113.6 ± 1.17 µM, 124.5 ± 0.64 µM, respectively) with IC50 values of 17.32 ± 0.76 and 109.41± 0.87 µM, respectively. In addition, molecular docking studies were performed to determine the binding modes and energies between PDZ-1 and the target enzymes.

Insights into the role of RAHB and IHB interactions for the structure- Activity relationship of caged xanthone Morellic Acid: Spectroscopic and DFT exploration, molecular docking, and molecular dynamics simulation studies as an Antituberculosis agent

The current study elaborates on experimental and simulated methods using density functional theory (DFT) to analyze the structure, electronic characteristics, and vibrational features of morellic acid, an isolate from Garcinia wightii. The in-depth examination of the stabilized structure indicates that the compound achieves equilibrium through conjugative, hyperconjugative, resonance-assisted hydrogen bonding (RAHB), and intramolecular hydrogen bonding (IHB) interactions, resulting in a well-supported conformation. The vibrational spectra were recorded, and the wavenumbers were comprehensively assigned using Potential Energy Distribution with a scaled quantum mechanical force field. Natural bond orbital (NBO) studies were utilized to calculate donor and acceptor bond interaction energy and electron densities. The TD-DFT computations were performed in solvent (chloroform) and gaseous phase, which agreed with the experimental values. Molecular electrostatic potential (MEP), reduced density gradient (RDG), electron localized function (ELF), and localized orbital locator (LOL) of the molecule were also analyzed. The molecular docking studies revealed that the compound holds great promise as a drug candidate for tuberculosis treatment, with the most thermodynamically stable binding score of -11.542 kcal/mol with 4BFS (protein of Mycobacterium tuberculosis PanK). The molecular dynamics (MD) simulation studies examined the stability and hydrogen bonding system of the ligand-protein complex formed between the molecule and the essential target protein for 100 ns. The findings revealed that the complex remained stable with minimal fluctuations throughout the simulation, suggesting that the molecule may prevent tuberculosis and be used as a treatment candidate.

Vibrational assignments of cyclic dimers and inter-monomers of adenine relating FT-IR, FT-Raman and UV spectra with SQMFF and DFT calculations

In this work, three different cyclic dimers and a tetramer of adenine taken from the experimental structure determined by X-ray diffraction have been studied by combination of experimental FT-IR, FT-Raman and UV–Visible spectra with hybrid B3LYP/6–311++G** and scaled quantum mechanical force field (SQMFF) calculations in order to perform the complete assignments of bands observed in the vibrational spectra. The characteristics of different N-H···N interactions of those three cyclic structures together with the group of IR bands observed between 2865 and 2599 cm−1 have been elucidated considering the tetrameric structure. The cyclic dimers and the tetramer of adenine confirm that the bands observed between 2865 and 2599 cm−1 are not due to N-H···N interactions but to bands of combination, as was previously suggested. The experimental available deuterated IR and terahertz spectra have allowed the complete assignments of regions of higher and lower wavenumbers. Good correlations were acquired comparing the theoretical IR, Raman and UV spectra of three species and the tetramer with the analogous experimental ones, suggesting the presence of all species in both phases. Vibronic bands are observed in the electronic spectra when adenine concentration is increased in aqueous solution evidencing the presence of monomer, tautomers and dimers, as reported by different studies. Similar characteristics of H bonds interactions are predicted for dimers 1 and 2 but different from the dimer 3, as revealed by using NBO and AIM calculations. Different scaled force constants values were found for the cyclic dimers 1 and 2, as compared to the corresponding to dimer 3.

Effect of Long-Range Corrections on Intermolecular Interactions and Vibrational Assignments of Ethylene Oxide Dimer. A Combined DFT and SQFF Study

Theoretical structural and vibrational study for the ethylene oxide dimer have been performed by using the experimental structure determined by X-ray diffraction, the vibrational spectra and, the functional hybrids B3LYP/6-311++G** and WB97XD/6-311++G** methods. Here, the effects of dispersion on intermolecular interactions and on complete assignments of infrared and Raman spectra of dimer have been performed combining the Pulay´s scaled quantum mechanical force field (SQMFF) methodology with those two levels of calculations in order to fit the theoretical wavenumbers values to the experimental ones. Calculations including long-range corrections have revealed similar optimized energy, volume and frequencies to calculated with the B3LYP/6-31G* method, lower correlations in the geometrical parameters, higher stabilization energy, higher values in the topological parameters and higher scaled force constants than the obtained at B3LYP/6-311++G** level. Natural bond order (NBO) and atoms in molecules theory (AIM) studies with both methods reveal two types of intermolecular interactions (C-O···H and C-O···O) in the ethylene oxide dimer in accordance with the bands observed in the experimental Raman spectrum at low temperatures and with the experimental structure determined at 100 K. The nature of those interactions and their topological properties were studied by using NBO and AIM calculations. The studied properties for the ethylene oxide dimer were analyzed and compared with those obtained for the monomer. Similar assignments of the vibrational modes for dimer were obtained using the three different methods.

VIBRATIONAL SPECTROSCOPIC STUDY OF PYRIDINE AND PYRIMIDINE LIGANDS COORDINATED WITH ANTIMONY (III) COMPLEXES: INSIGHTS FROM DFT CALCULATIONS

By employing the Scaled Quantum Mechanics Force Field (SQMFF) methodology, a comprehensive analysis was conducted to assign the vibrational spectra of three antimony (III) compounds, [1a-3a], that possess pyridine and pyrimidine ligands. The potential energy distribution (PED) was calculated and utilized to assign the IR spectra of the antimony (III) compounds. The theoretical frontier molecular orbital descriptors, the partial and total density of state distribution (TDOS, PDOS), molecular electronic potential surface map (MEP), nonlinear optical properties (NLO) of these complexes also were computed and investigated. The DFT/B3LYP/GEN (C, H, N, Cl: 6-31G(d,p) and Sb: LanL2DZ) level was utilized for all DFT calculations using the Gaussian 09W program. Furthermore, theoretical frontier molecular orbital descriptors, including electronegativity, chemical potential, softness, electrophilicity index, and electron affinity for six antimony (III) compounds were calculated ([1a/1b-3a/3b]). The results showed that, the ionization potential energy value of the [3a], which had the lowest experimental Leishmania activity, was also found to be the lowest among the others.

Quantum computational, Spectroscopic investigations on benzofuranylcarbonylpyrazolopyridine by DFT/TD-DFT: Synthesis, Structure, NBO and NLO research

Reaction of 4-methoxy-5-oxo-5H-furo[3,2-g] chromene-6-carboxaldehyde (1) with 5-amino-2,4-dihydro-3H-pyrazol-3-one (2) afforded the novel 5-(6-hydroxy-4-methoxy-1-benzofuran-5-ylcarbonyl)-3-hydroxy-1H-pyrazolo[3,4-b]pyridine (3, BFCPP). The experimental and theoretical quantum computations (optimized structure, IR, NMR and UV-Vis.) investigation of the current compound were performed using DFT theory at B3LYP functional and 6–311++G(d,p) basis set. The complete analysis of the vibrational spectra was taken with the aid of normal coordinate analysis followed by scaled quantum mechanical force field methodology. The theoretical NMR was achieved in DMSO-d6 as a solvent, while the IR and optimized calculations were done in the gas phase. A kind of solutions were used to discover the UV-Visible spectrum using the TD-DFT method. The stability of the current molecule occurred from hyper conjugative interactions leading to its nonlinear optical activity. Also, the charge delocalization was analyzed using natural bond orbital technique. Mulliken atomic charge and molecular electrostatic potential (MEP) are also calculated. HOMO–LUMO energy gap value indicates the probability of charge transfer within the molecule. The thermodynamic properties at different temperatures are also analyzed.

Optimized Quantum Drude Oscillators for Atomic and Molecular Response Properties.

The quantum Drude oscillator (QDO) is an efficient yet accurate coarse-grained approach that has been widely used to model electronic and optical response properties of atoms and molecules as well as polarization and dispersion interactions between them. Three effective parameters (frequency, mass, and charge) fully characterize the QDO Hamiltonian and are adjusted to reproduce response properties. However, the soaring success of coupled QDOs for many-atom systems remains fundamentally unexplained, and the optimal mapping between atoms/molecules and oscillators has not been established. Here we present an optimized parametrization (OQDO) where the parameters are fixed by using only dipolar properties. For the periodic table of elements as well as small molecules, our model accurately reproduces atomic (spatial) polarization potentials and multipolar dispersion coefficients, elucidating the high promise of the presented model in the development of next-generation quantum-mechanical force fields for (bio)molecular simulations.

Experimental and theoretical vibrational spectral Investigations, structural conformations, DFT estimations and docking studies of antibacterial drug Nitrilotriaceticacid

Nitrilotriaceticacid (NTA) was utilised without additional purification after being bought from Sigma Aldrich Chemical Company in powdered form with 99% purity. Density Functional Theory calculations at B3LYP with a 6-311++G (d,p) level were performed to gain knowledge of molecule geometries, harmonic vibrational spectra, and molecular docking analysis. Vibrational spectral investigations have been carried out with the aid of Normal Coordinate Analysis on the basis of potential energy distribution (PED) of each mode, which helps us to attain a quantitative as well as qualitative analysis of IR and Raman spectra followed by empirical scaled quantum mechanical force field methodology. Natural bond orbital analysis, Fukui analysis, RDG analysis, and Mulliken’s net charges have also been predicted. FMO's energy gap predicts the occurrence of charge transport within molecule. UV–Visible spectral analyses of NTA have been examined by experimental and theoretical calculations. By mapping electron density isosurface with an electrostatic potential surface (ESP), information about the size, shape, charge density distribution, and site of chemical reactivity of the molecules has been acquired. ELF and LOL maps portrayed topological aspects of NTA which also have been depicted. Hyperpolarizability values are in good agreement revealing that these compounds could be employed in electro optical applications. Antibacterial activity reveals that NTA have been found to exhibit antibacterial effects. Docking simulation has been carried out for the optimized ligand molecule to identify binding energy and coupling with protein molecule. NTA molecule underwent a drug likeness test utilising Lipinski's criterion, and using ADMET contour, the molecule is recommended for inclusion in pharmaceuticals.

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Density functional studies of antimony complexes derived from carboxamide ligands

The anti-leishmanial activity of antimony (III) complexes [1a-3a] bearing carboxamide ligands has been reported in the literature. In this study, a complete assignment of the vibrational spectra of these complexes was performed using the Scaled Quantum Mechanics Force Field (SQMFF) methodology in the solid phase at the DFT/ B3LYP/ LanL2DZ level. Quantum chemical descriptors (FMO, hardness, softness, etc) of these complexes were calculated to investigate the relationship between the calculated descriptors and their anti-leishmanial activities. As the softness of the complexes increased, the anti-leishmanial activity also increased. No correlation was found between the vibrational frequencies of the complexes and anti-leishmania activity.

QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations.

Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand complexes include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v.2), has demonstrated success in predicting unbinding (koff) kinetics by employing molecular dynamics (MD) simulations in regions closer to the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve the simulation efficiency and parallelization. To date, all MD simulations are run using general molecular mechanics (MM) force fields. The accuracy of calculations can be further improved by incorporating quantum mechanical (QM) methods into generating system-specific force fields through reparameterizing ligand partial charges in the bound state. The force field reparameterization process modifies the potential energy landscape of the bimolecular complex, enabling a more accurate representation of the intermolecular interactions and polarization effects at the bound state. We present QMrebind (Quantum Mechanical force field reparameterization at the receptor-ligand binding site), an ORCA-based software that facilitates reparameterizing the potential energy function within the phase space representing the bound state in a receptor-ligand complex. With SEEKR2 koff estimates and experimentally determined kinetic rates, we compare and interpret the receptor-ligand unbinding kinetics obtained using the newly reparameterized force fields for model host-guest systems and HSP90-inhibitor complexes. This method provides an opportunity to achieve higher accuracy in predicting receptor-ligand koff rate constants.

Spectroscopic, Vibrational and Topology Analysis of (2R, 3R) - Butanediol bis (Methanesulfonate)

Objectives: To find the (2R, 3R)-Butanediol bis (methanesulfonate) (BBM) to be the most bioactive through DFT calculations and multi-spectroscopic investigations. Methods: BBM molecule was characterized by multi-spectroscopic investigations (FT-IR, FT-Raman, UV-Vis) and quantum chemical computations employing density functional theory with wB97XD and cam-B3LYP basis functional. Findings: The assignments of vibrational spectral features were made with the help of Gar2ped, which incorporates the Scaled Quantum Mechanical Force Field (SQMFF) methodology. The absolute energy gap between the frontier molecular orbitals (HOMO and LUMO) at room temperature and reactivity descriptors confirm that the molecule BBM is chemically active, to realize the charge transfer within the molecule and shows the best bioactive molecule. Moreover, the weak intramolecular interaction and evaluate the intermolecular interaction (hydrogen bonds) were revealed from quantum topological atoms in molecules and reduced density gradient plots. Novelty: BBM molecule was found to very good bioactive molecules, given the results of vibrational, topological, quantum computational methods and RDG analysis. Keywords: BBM; DNA; SQMFF; HOMO; LUMO

Structural and vibrational investigation of Cis-Trans isomers of potent insecticide allethrin.

In this research, the optimised structural and vibrational properties of cis-trans isomers of powerful insecticide allethrin were theoretically studied in gas phase and in aqueous and ethanol solutions by using hybrid B3LYP/6-311 + + g(d,p) level of theory. The results revealed that the permittivity of solvent has influence on the properties of both isomers, thus, higher dipole moments and solvation energies are observed in water, a solvent of higher permittivity (78.355) than ethanol. Complete vibrational assignments of both isomers were done by combining the experimental IR spectrum of allethrin with the scaled quantum mechanical force field (SQMFF) methodology and the determination of corresponding scaled force constants in gas phase and aqueous solution are reported. Different signs of dihedral O2C10C6C4 angles of both isomers (negative in cis and positive in trans) support the differences in the vibrational assignments. Natural bond orbital (NBO) calculations suggest that both isomers are highly stable in gas phase and aqueous solution and that the side chains and five member's rings are involved in the n → σ* interactions. However, atoms in molecules (AIM) studies reveal a higher stability of form cis in both media than the trans one. Merz-Kollman (MK), Mulliken and natural population atomic (NPA) charges for both isomers support the higher hydration of trans isomer in aqueous media and, hence, the higher solvation energy in water (ΔGC/ZPVE = - 80.29kJ/mol). Changes in the bond orders of O and C atoms of side chain are observed in water as a consequence of hydration. The higher stability of the cis form in the above solutions could be explained by the lower solvation energy in water, as supported by AIM calculations. The studies of frontier orbital reveal that the cis form in both media is sligthly more reactive than the trans form.

Hydrogen bonding interaction and topological insights of the electron localization/delocalization of l- arginine acetate

The vibrational spectral studies of the semi-organic material l- arginine acetate (LAA) are carried out with the help of density functional calculations to derive the equilibrium geometry as well as the vibrational wavenumbers and intensities of the spectral bands. The vibrational spectrum assignments are performed using normal coordinate analysis (NCA) in accordance with the scaled quantum mechanical force field approach (SQMFF). Vibrational spectra confirm the COO- modes split due to intra- and intermolecular association based on C–O….H, N–H….O, and O–H⋯O hydrogen bonding in the molecule, which lowers carboxylate wavenumbers. The natural bond orbital (NBO) analysis and DFT computations also confirm the occurrence of strong intra and intermolecular N–H⋯O and O–H⋯O ionic hydrogen bonding between charged species, providing the non-centrosymmetric structure in the LAA crystal.

Vibrational Study of Mono and Diprotonated Species of Potent Anti-acid Ranitidine Hydrochloride Combining DFT with SQMFF Calculations

Structural and vibrational studies of mono (M) and diprotonated (D) species of ranitidine hydrochloride (RH) have been performed by combining B3LYP/6-31G* calculations with the scaled quantum mechanical force field (SQMFF) methodology. Four M structures in the gas phase and aqueous solution and two D E/Z and Z/E isomers in solution were considered. The M and D free base, cationic, and hydrochloride species show higher dipole moment values and expansion of volumes in solution, while higher solvation energies are predicted for both D (E/Z) and (Z/E) species. NBO and AIM studies suggest high stabilities of D (Z/E) cationic and hydrochloride species in solution. Gap values show that the M and D species are the most reactive in both media. M and two D forms were completely assigned, and their force constants were reported. The D hydrochloride (E/Z) form shows two IR bands at 2718 and 2625 cm-1 assigned to νN6-H34 and νN5-H44 stretching modes where the formation of O3-H34···N6 bond justifies the strong shifting of N6-H34 stretching mode towards lower wavenumbers. The IR bands at 2563, 2515, and 2475 cm-1 assigned to the two D species, together with the absence of an intense band at 1764 cm-1, show clearly that M species is not present in the solid phase, but the two D hydrochloride (E/Z) and (Z/E) species.

Scaled in Cartesian Coordinates Ab Initio Molecular Force Fields of DNA Bases: Application to Canonical Pairs.

The model of Regularized Quantum Mechanical Force Field (RQMFF) was applied to the joint treatment of ab initio and experimental vibrational data of the four primary nucleobases using a new algorithm based on the scaling procedure in Cartesian coordinates. The matrix of scaling factors in Cartesian coordinates for the considered molecules includes diagonal elements for all atoms of the molecule and off-diagonal elements for bonded atoms and for some non-bonded atoms (1–3 and some 1–4 interactions). The choice of the model is based on the results of the second-order perturbation analysis of the Fock matrix for uncoupled interactions using the Natural Bond Orbital (NBO) analysis. The scaling factors obtained within this model as a result of solving the inverse problem (regularized Cartesian scale factors) of adenine, cytosine, guanine, and thymine molecules were used to correct the Hessians of the canonical base pairs: adenine–thymine and cytosine–guanine. The proposed procedure is based on the block structure of the scaling matrix for molecular entities with non-covalent interactions, as in the case of DNA base pairs. It allows avoiding introducing internal coordinates (or coordinates of symmetry, local symmetry, etc.) when scaling the force field of a compound of a complex structure with non-covalent H-bonds.

Structural study and vibrational assignments of FT-IR and FT-Raman spectra of powerful pesticide 2,4’-DDT. Its comparison with 4,4’-DDT

In this work, the S(+) and R(-) forms of powerful pesticide 2,4’-DDT have been experimentally characterized by using the experimental FT-IR and FT-Raman spectra in the solid phase accomplished with calculations derived from the density functional theory (DFT) together with the 6-31G* and 6-311++G** basis sets. The optimizations in gas phase with both levels of calculations reveal that the R(-) form is the most stable of 2,4’-DDT, as was experimentally observed in the solid state. Here, the geometrical parameters, atomic charges, bond orders, main delocalization energies, the topological parameters, force constants and the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps for both forms of 2,4’-DDT were compared with reported for R-4,4’-DDT. Complete assignments of 78 vibration normal modes for R-2,4’-DDT were performed by using the scaled quantum mechanical force field (SQMFF). Comparisons between both DDT derivatives show that the structural change of one Cl atom in para position in 4,4’-DDT to ortho position in R-2,4’-DDT produce changes in the assignments, intensities and positions of IR bands between 1400 and 1200 cm−1 region while a set of bands in the region close to 1000 cm−1 are only observed in the Raman spectra of R-2,4’-DDT. The vibration CCl3 and C-Cl modes of groups or bonds common to the two DDT species are predicted in practically the same positions. Natural bond orbital (NBO) and atoms in molecules (AIM) calculations evidence higher stability of form R-2,4’-DDT as compared with the S one while the gap values support lower reactivities of both forms of 2,4’-DDT as compared with 4,4’-DDT. Finally, the scaled force constants related to diphenyl rings and trichloroethane groups of both derivatives present practically the same values.