Hybrid QM Research Articles

Hybrid RPA:DFT Approach for Adsorption on Transition Metal Surfaces: Methane and Ethane on Platinum (111).

The hybrid QM:QM approach is extended to adsorption on transition metal surfaces. The random phase approximation (RPA) as the high-level method is applied to cluster models and, using the subtractive scheme, embedded in periodic models which are treated with density functional theory (DFT) that is the low-level method. The PBE functional, both without dispersion and augmented with the many-body dispersion (MBD), is employed. Adsorption of methane and ethane on the Pt(111) surface is studied. For methane in a 2 × 2 surface cell, the hybrid RPA:PBE and RPA:PBE+MBD results, -14.3 and -16.0 kJ mol-1, respectively, are in close agreement with the periodic RPA value of -13.8 kJ mol-1 at significantly reduced computational cost (factor of ∼50). For methane and ethane, the RPA:PBE results (-14.3 and -17.8 kJ mol-1, respectively) indicate underbinding relative to energies derived from experimental desorption barriers for relevant loadings (-15.6 ± 1.6 and -27.2 ± 2.9 kJ mol-1, respectively), whereas the hybrid RPA:PBE+MBD results (-16.0 and -24.9 kJ mol-1, respectively) agree with the experiment well within experimental uncertainty limits (deviation of -0.4 ± 1.5 and +2.3 ± 2.9 kJ mol-1, respectively). Finding a cluster that adequately and robustly represents the adsorbate at the bulk surface is important for the success of the RPA-based QM:QM scheme for metals.

Spectroscopic and Computational pH Study of NiII and PdII Pyrrole-Imine Chelates with Human Serum Albumin.

Human serum albumin (HSA) efficiently transports drugs in vivo: most are organic. Therefore, it is important to delineate the binding of small molecules to HSA. Here, for the first time, we show that HSA binding depends not only on the identity of the d8 metal ion, NiII or PdII, of their complexes with bis(pyrrole-imine), H2PrPyrr, but on the pH level as well. Fluorescence quenching data for native and probe-bound HSA showed that sites close to Trp-214 (subdomain IIA) are targeted. The affinity constants, Ka, ranged from ~3.5 × 103 M-1 to ~1 × 106 M-1 at 37 °C, following the order Pd(PrPyrr) > Ni(PrPyrr) at pH levels of 4 and 7; but Ni(PrPyrr) > Pd(PrPyrr) at a pH level of 9. Ligand uptake is enthalpically driven, dependent mainly on London dispersion forces. The induced CD spectra for the protein-bound ligands could be simulated by hybrid QM:MM TD-DFT methods, allowing us to delineate the binding site of the ligands and to prove that the metal chelates neither decompose nor demetallate after uptake by HSA. The transport and delivery of the metal chelates by HSA in vivo is therefore feasible.

Complexities of the Interaction of NiII, PdII and PtII Pyrrole‐Imine Chelates with Human Serum Albumin**

AbstractHuman serum albumin (HSA) efficiently transports drugs in vivo: most are organic. Here, HSA binding affinity and site specificity are shown to depend on the identity of the d8 metal ion in NiII, PdII and PtII chelates of the bis(pyrrole‐imine) ligand H2PrPyrr. Fluorescence quenching data for native and probe‐bound HSA showed sites close to Trp‐214 (subdomain IIA) are targeted. The Stern‐Volmer constants, KSV, ranged from 104 M−1 to 105 M−1 while the affinity constants, Ka, ranged from ∼3.5×103 M−1 to ∼1×106 M−1 at 37 °C, following the order Pd(PrPyrr) > Pt(PrPyrr) > Ni(PrPyrr) > H2PrPyrr. Ligand uptake is enthalpically driven, hinging mainly on London dispersion forces. Induced CD spectra for the protein‐bound ligands could be simulated by hybrid QM:MM TD‐DFT methods, proving that the metal chelates neither decompose nor demetallate after uptake by HSA. Transport and delivery of the metal chelates by HSA in vivo could therefore be feasible.

Spectroscopic and computational study of the interaction of Pt(II) pyrrole-imine chelates with human serum albumin.

Three bis(pyrrolide-imine) Pt(II) chelates were synthesised and characterized with different bridging alkyl groups, specifically 2-hydroxypropyl (1), 2,2-dimethylpropyl (2), and 1,2-(S,S)-(+)-cyclohexyl (3). Novel compounds 1 and 2 were analysed by single-crystal X-ray diffraction (space group P1̄). The asymmetric unit of 1 comprises three independent molecules linked by hydrogen bonds involving the OH groups, forming a trimeric supramolecular structure. The Pt(II) chelates were reacted with human serum albumin (HSA) to investigate how the ligand bound to the Pt(II) ion influences the compound's affinity for HSA. Fluorescence quenching data obtained for native HSA and HSA bound to site-specific probes (warfarin, subdomain IIA; ibuprofen, subdomain IIIA) indicated that the three Pt(II) chelates bind close enough (within ∼30 Å) to Trp-214 to quench its intrinsic fluorescence. The bimolecular quenching constant (kq) was 103-104 -fold higher than the maximum diffusion-controlled collision constant in water (1010 M s-1) at 310 K, while the affinity constants, Ka, ranged from ∼5 × 103 to ∼5 × 105 at 310 K, and followed the order 1 > 3 > 2. The reactions of 1 and 3 with HSA were enthalpically driven, while that for 2 was entropically driven. Macromolecular docking simulations (Glide XP) and binding site specificity assays employing site-specific probes and UV-vis CD spectroscopy indicated that 1 and 2 target Sudlow's site II in subdomain IIIA, minimally perturbing the tertiary structure of the protein. Well-resolved induced CD signals from 1 and 2 bound to HSA in subdomain IIIA were adequately simulated by hybrid QM:MM TD-DFT methods. We conclude that the structure of the bis(pyrrolide-imine) Pt(II) chelate measurably affects its uptake by HSA without detectable decomposition or demetallation. Such compounds could thus serve as metallodrug candidates capable of utilising an HSA-mediated cellular uptake pathway.

TD‐DFT modeling of electronic spectra of biliverdins in different environments

AbstractNon covalent biliproteins are found in a growing number of living organisms and even in viruses, such as SARS‐CoV‐2. Unlike the well described covalent biliproteins, such as the phytochromes, they present a vast structural and functional diversity, and often with limited experimental information. A very important tool (and sometimes the only one available) to study these systems is the UV–Vis spectrum, which is modulated both by conformational changes of the biliverdin chromophore and specific interactions with the apoprotein. In this work we present a theoretical study of the microscopic determinants of the UV–Vis spectrum of these compounds through the use of hybrid QM(TD‐DFT)/MM techniques and molecular dynamics simulations. Comparing our results with existing experimental data, we prove that it is possible to predict spectroscopic properties, such as relative position and intensity ratio of main bands, with affordable methods, and to provide a microscopic explanation of them. This systematic information can be very useful for the study of described biliproteins or for those yet unknown.

On the Accuracy of QM/MM Models: A Systematic Study of Intramolecular Proton Transfer Reactions of Amino Acids in Water.

This work presents a systematic assessment of QM/QM' and QM/MM models with respect to direct QM calculations for the tautomerization (neutral to zwitterion) reactions of amino acids (glycine, alanine, valine, aspartate, and neutral and protonated histidine) solvated in a 160 water cluster. The effect of varying QM region size and choice of embedding potentials, including fixed-charge and polarizable molecular mechanics force fields (TIP3P and EFP) and various semiempirical QM methods (PM7, GFN2-xTB, DFTBA, DFTB3, HF-3c, and PBEh-3c), on the accuracy of the models was examined. A surprising finding was that molecular mechanics force fields outperformed many of the semiempirical methods. Generally, the errors in the QM/QM' and QM/MM models converge slowly with respect to the QM region size, requiring 50 or more waters to be included in the QM region before the error in the model falls below 1 kcal mol-1 of its pure QM result. Different QM region selection schemes were also compared, and it was found that selection based on Natural Population Analysis (NPA) atomic charges significantly reduced the error in the QM/QM' and QM/MM models particularly if a low-quality embedding potential was used. It is envisaged that these results will be useful for the development of future hybrid QM models.

Adsorption and cracking of propane by zeolites of different pore size

A hybrid QM:QM method (MP2:(PBE+D2) + ΔCCSD(T)) is employed that reaches chemical accuracy (±4 kJ mol−1) for periodic systems. Three mechanisms are considered and evidence is produced that cracking proceeds via protonation of a CC bond at the Brønsted acid site. For H-FER, H-MFI, and H-CHA, the deviations between predictions (uncertainty ± 4 kJ mol−1) and experiment (error ± 5 kJ mol−1) are between −3 and +8 kJ mol−1. The predicted apparent enthalpy barriers for H-FER, H-MFI, H-CHA, and H-FAU at 650 K are 153, 153, 160, and 182 kJ mol−1, respectively. Their variation with the pore size is dominated by the adsorption enthalpies (−55, −47, −40, and −29 kJ mol−1, respectively), whereas the intrinsic enthalpy barriers vary within a narrow range of 10 kJ mol−1 only. Routine PBE+D2 calculations show large errors, −16 to −20 and −40 to −60 kJ mol−1 for adsorption enthalpies and enthalpy barriers, respectively.

Exploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation

HIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6-31++G(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease.

Intersystem crossing in thiobases proceeds by a dark intermediate state

4-thiouracil (4TU) is studied by transient absorption spectroscopy employing sub-20 fs UV-pulses and hybrid QM(CASPT2) / MM(AMBER) computations (static and dynamic), evidencing that, along the photoexcited relaxation pathway, intersystem crossing originates from a dark intermediate state.

QM–MM Ehrenfest dynamics from first principles: photodissociation of diazirine in aqueous solution

This article describes an implementation of Ehrenfest molecular dynamics based on TDDFT and Gaussian basis sets, optimized for hybrid QM–MM simulations in GPU. The present method makes use of the equations of motion proposed by Chen et al. (J Chem Phys 135:044126, 2011), which, at variance with previous formulations of the Ehrenfest dynamics, takes into account the movement of the localized basis functions, thus improving accuracy and energy conservation. This methodology is used to explore the evolution and the stability of excited state dynamics for two different constructions of the initial excited state, consisting in the linear response TDDFT $$S_1$$ solution, and in the ground state density matrix where the HOMO–LUMO occupancies have been switched, which is a widespread approach to model photoexcitation in electron dynamics simulations. It is found that the second kind of starting state leads to a larger numerical noise and to a poorer stability of the dynamics, aside from “awakening” inner electronic modes that become manifest in the frequency spectrum, and which are absent if the dynamics departs from the linear response TDDFT density matrix. Then, the method is applied to investigate the photodissociation of the diazirine molecule, CH $$_2$$ N $$_2$$ , both in vacuum and in aqueous solution. Diazirine decomposes into carbene and molecular nitrogen upon irradiation with UV light, and for this reason it has been widely adopted to photolabel biomolecules through the insertion of carbenes in the macromolecular surface. Our simulations suggest that the quantum yield of the dissociative reaction experiences a decrease in solution with respect to the gas phase, that can be understood in terms of the vibrational relaxation facilitated by the solvent molecules. Besides, the present results indicate that the isomerization and dissociation mechanism occur fully on the $$S_1$$ excited state.

Ab initio study of methanol and ethanol adsorption on Brønsted sites in zeolite H-MFI.

We examine the interaction of methanol and ethanol with a bridging OH group of H-MFI (Al12-O20(H)-Si3 site). The computational standard approach for molecule-surface interaction uses density functional theory with inclusion of dispersion for energies and harmonic vibrational frequencies for entropies and finite temperature effects for enthalpies. At 300 K, this yields -117 and -135 kJ mol-1 for adsorption enthalpies of methanol and ethanol, respectively, and 59 and 61 kJ mol-1, respectively for their entropy terms -T·ΔS. To reach chemical accuracy (±4 kJ mol-1) we go beyond this approach. The energies are calculated using a hybrid QM:QM scheme (QM - quantum mechanics) which combines plane-wave density functional theory accounting for the periodicity of the system with wave function-based methods (Møller-Plesset perturbation and Coupled Cluster theories). Finite temperature and entropy contributions are calculated from anharmonic vibrational partition functions. This yields as final predictions for methanol and ethanol -84 and -104 kJ mol-1, respectively, for the enthalpies of adsorption, 56 and 48 kJ mol-1, respectively, for the -T·ΔS term, and -28 and -56 kJ mol-1, respectively, for the Gibbs free energies at 300 K.

Resolving Ultrafast Photoinduced Deactivations in Water-Solvated Pyrimidine Nucleosides.

For the first time, ultrafast deactivations of photoexcited water-solvated pyrimidine nucleosides are mapped employing hybrid QM(CASPT2)/MM(AMBER) optimizations that account for explicit solvation, sugar effects, and dynamically correlated potential energy surfaces. Low-energy S1/S0 ring-puckering and ring-opening conical intersections (CIs) are suggested to drive the ballistic coherent subpicosecond (<200 fs) decays observed in each pyrimidine, the energetics controlling this processes correlating with the lifetimes observed. A second bright 1π2π* state, promoting excited-state population branching and leading toward a third CI with the ground state, is proposed to be involved in the slower ultrafast decay component observed in Thd/Cyd. The transient spectroscopic signals of the competitive deactivation channels are computed for the first time. A general unified scheme for ultrafast deactivations, spanning the sub- to few-picosecond time domain, is eventually delivered, with computed data that matches the experiments and elucidates the intrinsic photoprotection mechanism in solvated pyrimidine nucleosides.

Fast and accurate hybrid QM//MM approach for computing anharmonic corrections to vibrational frequencies

We have developed and tested a new time-effective and accurate hybrid QM//MM generalized second-order vibrational perturbation theory (GVPT2) approach. In this approach, two different levels of theory were used, a high level one (DFT) for computing the harmonic spectrum and a lower fast one (Molecular Mechanic) for the anharmonic corrections. To validate our approach, we used B2PLYP/def2-TZVPP as the high-level method, and the MMFF94 method for the anharmonic corrections as the low-level method. The calculations were carried out on 28 molecules (containing from 2 to 47 atoms) covering a broad range of vibrational modes present in organic molecules. We find that this fast hybrid method reproduces the experimental frequencies with a very good accuracy for organic and bio-molecules. The root-mean-square deviation (RMSD) is about 27 cm -1 while the full B3LYP/SNSD simulation reproduces the experimental values with a RMSD of about 41 cm -1. Concerning the computational time, the hybrid B2PLYP//MMFF94 approach considerably outperforms the full B3LYP/SNSD: for the larger molecule of our set (a dipeptide containing 47 atoms), the anharmonic corrections are 2300 times faster using hybrid MMFF94 rather than full B3LYP, which represents an additional computation time to the harmonic calculation of merely 9 %, instead of 32100 % with the full B3LYP approach. This time-effective and accurate alternative to the traditional GVPT2 approach will allow the spectroscopy community to explore anharmonic effects in larger biomolecules, which are generally unaffordable.

Revealing the active role of the terminal CNO moiety in the photochemical oxaziridine conversion process of some chemopreventive retinylnitrones through hybrid QM:QM and QM:MM ONIOM calculations

The QM:QM and QM:MM ONIOM calculations on the retinylnitrones(13-trans and 13-cis) have revealed the presence of low-lying CNO-kinked conical intersections (65–70kcal/mol above their ground states) on the nitrone-oxaziridine photo-conversion path. Following the directions of their gradient difference vectors, optimized oxaziridine structures were obtained at the CASSCF/6-31G*:HF/STO-6G and CASSCF/6-31G*:UFF (with electronic embedding) level taking the CNO moiety as the high-level part. Inclusion of dynamic correlation in the high-level shifts the oxaziridine energies to higher values by 12–23kcal/mol. A transition state (ΔEactivation=30kcal/mol) with imaginary frequency of 361icm−1 is found to be responsible for thermal E–Z isomerization of 13-trans compound.

DNA spontaneous mutation and its role in the evolution of GC-content: assessing the impact of the genetic sequence.

The structure of DNA is not constantly at its equilibrium point but evolves with time. It is generally accepted that evolution induces a decrease of the guanine-cytosine (GC) content and a concomitant increase of the adenine-thymine (AT) ratio through a biased GC → AT mutation process. Unfortunately, the mechanism behind this natural alteration of the stored genetic information is not fully understood. Here, we use a hybrid QM:QM' approach to assess the link between one of the sources of the spontaneous mutation, the so-called G*C* rare tautomers that arise from a double proton exchange between the bases, and the evolution of the GC-content. Our simulations indicate that the G*C* mutation is mainly accumulated in GC-rich regions rather than being randomly spread, and consequently the GC → AT error tends to locate in coding fragments. That specific preference is indirectly induced by the base pairs containing the mutated point, as they tune the structure of the first hydration-shell that solvates the reactive base pair undergoing tautomerisation. The reorganisation of the explicit water molecules eventually modifies the energy barriers as well as the stability of the genetic error during the process.

One‐electron addition on short‐loop selenylsulfide and diselenide‐linked biomolecules: From diethyldichalcogens to Grx3‐like selenopeptides

AbstractOne‐electron uptake by thiaselenide or diselenide linkages of a series of short‐loop selenopeptides, is examined by means of hybrid QM:QM′ and QM:MM calculations. A special emphasis is given to the identification of key factors tuning adiabatic electron affinity, in comparison with established trends for disulfides. The conclusions are threefold: first, electron capture is intrinsically favored by 0.20 and 0.36 eV upon sulfur‐to‐selenium mono‐ or bi‐substitution. This order of reactivity, established on diethyldichalcogens, is globally transferable to linear dipeptides, with a dramatic increase of ∼1eV of adiabatic electron affinities. Cyclization impact is then quantified along a representative set of short‐loop peptides: conformational strain tends to reinforce dichalcogen propensity to act as an “electron buffer,” although this contribution is attenuated for seleno‐containing linkages because of their longer equilibrium distance. Collective electrostatic effects, such as the dipole created by a N‐terminal α‐helix, result in the same shifting, e.g., ∼1eV as a dodecalanine is grafted onto a given tetrapeptide. Structural features for neutral and radical anion species are also analyzed, in line with their spectroscopic aftermaths. This analysis delineates some useful trends for assisting design of seleno agents and artificial enzymes. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

Experimental and Theoretical Investigation of the First Overtone Spectrum of 1,3,5-Trinitrotoluene

Vibrational overtone spectroscopy is a powerful tool for studying intramolecular and intermolecular interactions. We report on a combined experimental and modeling study of the C-H stretch first overtone of bulk 1,3,5-trinitrotoluene (TNT) and TNT on fumed-silica powder. We recorded the overtone spectra by laser photoacoustic spectroscopy and compared them with those predicted with the harmonically coupled anharmonic oscillator model in the 5600-6600 cm(-1) region. The model systems included single molecules and hybrid quantum and molecular mechanical (QM:MM) clusters to account for the effects of intermolecular interactions on the observed spectra. We performed the hybrid QM:MM calculations at the HF/6-31+G(d,p), B3LYP/6-31+G(d,p), and MP2/6-31+G(d,p) levels of theory and with the universal force field (UFF) to account for van der Waals and electrostatic effects from surrounding molecules. Overtone spectra calculated from the MP2 level of theory, using a HF/3-21+G* calculation to assign molecular charges in the MM layer, and the Merz-Singh-Kollman population analysis for assigning partial charge in the QM layer and determining the transition dipole moment agreed best with the experimental data.

Adsorption of small aromatic molecules on the (111) surfaces of noble metals: A density functional theory study with semiempirical corrections for dispersion effects

The adsorption of benzene, thiophene, and pyridine on the (111) surface of gold and copper have been studied using density functional theory (DFT). Adsorption geometries and energies as well as the nature of bonding have been analyzed and compared to experimental results. Dispersion effects between neighboring molecules and between molecules and the surface have been taken into account via a semiempirical C(6)R(-6) approach. The C(6) coefficients for metal atoms have been deduced using both atomic properties and a hybrid QM:QM approach. Whereas the pure DFT calculations underestimate the adsorption energies significantly, a good agreement with experimental results is obtained using the DFT-D method based on the QM:QM hybrid approach.

Hybrid Quantum Mechanical/Molecular Mechanical Investigation of the β-1,4-Galactosyltransferase-I Mechanism

The enzyme beta-1,4-galactosyltransferase-1 (beta4Gal-T1) catalyzes the transfer of a galactose residue from UDP-Gal to the C4-hydroxyl group of N-acetylglucosamine. The catalytic mechanism of beta4Gal-T1 was investigated using the hybrid quantum mechanical/molecular mechanical (QM/MM) method, with the QM portion containing 253 atoms treated with density functional theory (DFT) at the BP/DZP and BP/TZ2P levels. The remaining parts of the beta4Gal-T1 complex, 4527 atoms in all, were modeled using the AMBER molecular force field. A theoretical model of the Michaelis complex was built using the X-ray structure of beta4Gal-T1 in a complex with the donor or acceptor substrate, respectively. The hybrid QM(DFT)/MM calculations identified an S(N)2-type transition state for the nucleophilic attack of the O4(a) oxygen on the anomeric carbon C1 and the breaking of the C1-O1 glycosidic linkage. The activation barrier found for this process is 15 kcal/mol. In the transition state (TS) model, the sugar donor is partially cleaved from pyrophosphate, while nucleophilic oxygen O4(a) remains protonated with a low barrier hydrogen bond to the catalytic base D318. The structure of TS is characterized by the O4(a)-C1 and C1-O1 distances of 2.703 and 2.092 A, respectively. When the obtained reaction sequence was used, the nature of the captured intermediate resembling the transition state structure (PDB/2FYD) was elucidated. This modeling QM/MM study has provided detailed insight into the mechanism of the Gal transfer catalyzed by beta4Gal-T1 and has supplied further evidence for a concerted S(N)2-type displacement mechanism employed by inverting glycosyltransferases.

Electrostatic Control of the Photoisomerization Efficiency and Optical Properties in Visual Pigments: On the Role of Counterion Quenching

Hybrid QM(CASPT2//CASSCF/6-31G*)/MM(Amber) computations have been used to map the photoisomerization path of the retinal chromophore in Rhodopsin and explore the reasons behind the photoactivity efficiency and spectral control in the visual pigments. It is shown that while the electrostatic environment plays a central role in properly tuning the optical properties of the chromophore, it is also critical in biasing the ultrafast photochemical event: it controls the slope of the photoisomerization channel as well as the accessibility of the S(1)/S(0) crossing space triggering the ultrafast decay. The roles of the E113 counterion, the E181 residue, and the other amino acids of the protein pocket are explicitly analyzed: it appears that counterion quenching by the protein environment plays a key role in setting up the chromophore's optical properties and its photochemical efficiency. A unified scenario is presented that discloses the relationship between spectroscopic and mechanistic properties in rhodopsins and allows us to draw a solid mechanism for spectral tuning in color vision pigments: a tunable counterion shielding appears as the elective mechanism for L<-->M spectral modulation, while a retinal conformational control must dictate S absorption. Finally, it is suggested that this model may contribute to shed new light into mutations-related vision deficiencies that opens innovative perspectives for experimental biomolecular investigations in this field.