Computed Interaction Energies Research Articles

Toward Post-Hartree-Fock Accuracy for Protein-Ligand Affinities Using the Molecules-in-Molecules Fragmentation-Based Method.

The complexity and size of large molecular systems, such as protein-ligand complexes, pose computational challenges for accurate post-Hartree-Fock calculations. This study delivers a thorough benchmarking of the Molecules-in-Molecules (MIM) method, presenting a clear and accessible strategy for layer/theory selections in post-Hartree-Fock computations on substantial molecular systems, notably protein-ligand complexes. An approach is articulated, enabling augmented computational efficiency by strategically canceling out common subsystem energy terms between complexes and proteins within the supermolecular equation. Employing DLPNO-based post-Hartree-Fock methods in conjunction with the three-layer MIM method (MIM3), this study demonstrates the achievement of protein-ligand binding energies with remarkable accuracy (errors <1 kcal mol-1), while significantly reducing computational costs. Furthermore, noteworthy correlations between theoretically computed interaction energies and their experimental equivalents were observed, with R2 values of approximately 0.90 and 0.78 for CDK2 and BZT-ITK sets, respectively, thus validating the efficacy of the MIM method in calculating binding energies. By highlighting the crucial role of diffuse or small Pople-style basis sets in the middle layer for reducing energy errors, this work provides valuable insights and practical methodologies for interaction energy computations in large molecular complexes and opens avenues for their application across a diverse range of molecular systems.

Influence of N-protonation on electronic properties of acridine derivatives by quantum crystallography.

Applications of 9-aminoacridine (9aa) and its derivatives span fields such as chemistry, biology, and medicine, including anticancer and antimicrobial activities. Protonation of such molecules can alter their bioavailability as weakly basic drugs like aminoacridines exhibit reduced solubility at high pH levels potentially limiting their effectiveness in patients with elevated gastric pH. In this study, we analyse the influence of protonation on the electronic characteristics of the molecular organic crystals of 9-aminoacridine. The application of quantum crystallography, including aspherical atom refinement, has enriched the depiction of electron density in the studied systems and non-covalent interactions, providing more details than previous studies. Our experimental results, combined with a topological analysis of the electron density and its Laplacian, provided detailed descriptions of how protonation changes the electron density distribution around the amine group and water molecule, concurrently decreasing the electron density at bond critical points of N/O-H bonds. Protonation also alters the molecular architecture of the systems under investigation. This is reflected in different proportions of the N⋯H and O⋯H intermolecular contacts for the neutral and protonated forms. Periodic DFT calculations of the cohesive energies of the crystal lattice, as well as computed interaction energies between molecules in the crystal, confirm that protonation stabilises the crystal structure due to a positive synergy between strong halogen and hydrogen bonds. Our findings highlight the potential of quantum crystallography in predicting crystal structure properties and point to its possible applications in developing new formulations for poorly soluble drugs.

Locating Guest Molecules inside Metal-Organic Framework Pores with a Multilevel Computational Approach.

Molecular docking has traditionally mostly been employed in the field of protein-ligand binding. Here, we extend this method, in combination with DFT-level geometry optimizations, to locate guest molecules inside the pores of metal-organic frameworks. The position and nature of the guest molecules tune the physicochemical properties of the host-guest systems. Therefore, it is essential to be able to reliably locate them to rationally enhance the performance of the known metal-organic frameworks and facilitate new material discovery. The results obtained with this approach are compared to experimental data. We show that the presented method can, in general, accurately locate adsorption sites and structures of the host-guest complexes. We therefore propose our approach as a computational alternative when no experimental structures of guest-loaded MOFs are available. Additional information on the adsorption strength in the studied host-guest systems emerges from the computed interaction energies. Our findings provide the basis for other computational studies on MOF-guest systems and contribute to a better understanding of the structure-interaction-property interplay associated with them.

Influence of an N,N,N-Trimethyl-1-adamantyl Ammonium (TMAda+) Structure Directing Agent on Al Distributions and Pair Features in Chabazite Zeolite

While organic structure directing agents (OSDAs) are well known to have a directional influence on the topology of a crystallizing zeolite, the relationship between OSDA charge and siting of aliovalent ions on a primarily siliceous framework is unclear. Here, we explore the relationship between OSDA orientation, Al3+ siting, and lattice energy, taking as a model system CHA zeolite occluded with N,N,N-trimethyl-1-adamantyl ammonium (TMAda+) at a Si/Al ratio of 11/1. We use density functional theory calculations to parametrize a fixed-charge classical model describing van der Waals and electrostatic interactions between the framework and OSDA. We enumerate and explore all possible combinations of OSDA orientation and Al location (attending to Löwenstein’s rule) within a 36 T-site supercell. We find that interaction energies vary over 60 kJ/double-six-ring-unit (d6r). Further, analysis of configurations reveals that energies are sensitive to Al–Al proximity, such that low energies are associated with Al3+ pairs in 8-membered rings and higher energies are associated with Al3+ pairs in smaller 6- and 4-membered rings. Comparisons with Al siting inferred from CHA zeolite crystallized with TMAda+ suggest that these computed interaction energies are useful reporters of observed Al siting in CHA synthesized with TMAda+.

Multireference configuration interaction calculations on the FeS molecule

ABSTRACT High-level ab initio calculations for the A-X and the a-X band systems of the FeS molecule are here reported. For such, potential energy curves are calculated using the multireference configuration interaction (MRCI) method. Subsequently, the computed interaction energies were fitted to an analytical representation and a new set of spectroscopic parameters was derived. The calculations predict a dissociation energy of 27,015 cm for the X, in agreement with recent experimental measurements. The similarity between X and A is considerable, showing an energy separation of only 953 . The spin-orbit coupling (SOC) effect was considered by using the Breit-Pauli operator (). At the equilibrium distance, the obtained SOC constant for the ground state is (X)= −206.6 cm. The rotationless radiative lifetimes for the A and a excited states are in the orders of milli- and microseconds, respectively, indicating that the vibronic emissions of the A-X system are too weak to be observed.

Through-Bond-Driven Through-Space Interactions in a Fullerene C60 Noncovalent Dyad: An Unusual Strong Binding between Spherical and Planar π Electron Clouds and Culmination of Dyadic Fractals.

Hydrogen-bond-induced π-depletion as a criterion for π-stacking, a configurationally unique noncovalent strategy enabled an unconventional strong binding between the spherical N-fulleropyrrolidine (NFP) and the planar distributions of π electron clouds of three substituted pybates to form noncovalent fulleropyrrolidino-4-(pyrenyl) butanoate dyads of large computed interaction energies, varying between 37.49 and 44.93 kcal/mol. The geometrical distortion/bending of the alkyl tail of pybate in the noncovalent dyad was experimentally corroborated via UV-vis absorption spectroscopy, which translated into spectral broadening along with pronounced shifts in the n-π* transitions of the oxy-substituted pyrene in different solvents, ensuring through-bond interactions. Facile electron transfer through H-bond influenced the dynamic dispersive forces to be active, revealing the supremacy of through-bond over through-space interactions. The analyses of intermolecular forces using an absolutely localized molecular orbital-based energy decomposition analysis (ALMO-EDA) scheme revealed intricate insights into the intermolecular interactions and characteristic charge transfer; the dominance of forward electron transfer (pybate to NFP) over the reverse in offering stabilization was noted. Charge transfer was investigated further from natural bond orbital (NBO) and absolutely localized molecular orbital-based charge-transfer analysis (ALMO-CTA) methods, establishing the supremacy of donor-to-acceptor electron transfer over the reverse (acceptor-to-donor) one. The characteristic self-assembly of the noncovalent dyad in suitable solvents led to the formation of fractal networks via reaction-limited cluster aggregation with a fractal dimension of 2.37. Adoption of constrained molecular dynamics simulations indicated probable wrapping of pybates around NFP, leading to fractal-like assembly.

Structural, Computational and 3D Interaction Energy Calculations of the Compound 2-chloro-3-(1-napthyl)-5,5-dimethyl-2-cyclohexenone

Structural, Computational and 3D Interaction Energy Calculations of the Compound 2-chloro-3-(1-napthyl)-5,5-dimethyl-2-cyclohexenone

Olympicene as a high-performance sensor for lung irritants: A dispersion corrected DFT insight

Surge for the development of sensor for selective and accurate detection of toxic warfare agents especially lung irritants is increasing day by day. Herein, by using the DFT approach, we explored the sensing ability of olympicene C19H12 (OLY) for accurate detection of chlorine, chloropicrin, phosgene, and diphosgene. The computed interaction energies at ωB97M-V/def2-TZVP level of theory show that lung irritants are physiosorbed over the olympicene surface. The charge transfer interactions of all the complexes are predicted by charge decomposition analysis (CDA) and Natural bond orbital (NBO) analysis. The reduced density gradient (RDG) approach indicates the dominance of electrostatic hydrogen bonding interactions in the complexes through non-covalent interaction (NCI) analysis. Moreover, the sensitivity of olympicene towards lung irritants is illustrated by the reduction in HOMO-LUMO energy gaps. The SAPT2+ analysis reveals that the dispersion factor remained dominant for stabilization of analyte@OLY complexes. Recovery time of olympicene is calculated to reveal the reusability of sensor at different temperatures. The upshot of the current study affirms appreciable selectivity of olympicene towards lung irritants. All findings and their prospects will supply effective and practical guidelines for an experimentalist to construct highly sensitive sensors for toxic warfare agents using olympicene.

Capture of Gaseous Iodine in Isoreticular Zirconium-Based UiO-n Metal-Organic Frameworks: Influence of Amino Functionalization, DFT Calculations, Raman and EPR Spectroscopic Investigation.

A series of Zr-based UiO-n MOF materials (n=66, 67, 68) have been studied for iodine capture. Gaseous iodine adsorption was collected kinetically from a home-made set-up allowing the continuous measurement of iodine content trapped within UiO-n compounds, with organic functionalities (-H, -CH3 , -Cl, -Br, -(OH)2 , -NO2 , -NH2 , (-NH2 )2 , -CH2 NH2 ) by in-situ UV-Vis spectroscopy. This study emphasizes the role of the amino groups attached to the aromatic rings of the ligands connecting the {Zr6 O4 (OH)4 } brick. In particular, the preferential interaction of iodine with lone-pair groups, such as amino functions, has been experimentally observed and is also based on DFT calculations. Indeed, higher iodine contents were systematically measured for amino-functionalized UiO-66 or UiO-67, compared to the pristine material (up to 1211 mg/g for UiO-67-(NH2 )2 ). However, DFT calculations revealed the highest computed interaction energies for alkylamine groups (-CH2 NH2 ) in UiO-67 (-128.5 kJ/mol for the octahedral cavity), and pointed out the influence of this specific functionality compared with that of an aromatic amine. The encapsulation of iodine within the pore system of UiO-n materials and their amino-derivatives has been analyzed by UV-Vis and Raman spectroscopy. We showed that a systematic conversion of molecular iodine (I2 ) species into anionic I- ones, stabilized as I- ⋅⋅⋅I2 or I3 - complexes within the MOF cavities, occurs when I2 @UiO-n samples are left in ambient light.

Deciphering the curved profile of uranyl ions at the aqueous-organic interface by atomistic simulations

The acceptance of nuclear energy is due to the safe and clean operation of the reactor along with the proper reprocessing of the aqueous nuclear waste. In that context, extraction of uranyl ion form aqueous solution has an immense importance in the field of fuel reprocessing. The extraction of uranyl ion is the key step on which the efficiency of the reprocessing depends. Tri-isoamyl phosphate (TiAP) is proven to be a potential alternative of Tri-butyl phosphate (TBP) in the Plutonium Uranium Extraction (PUREX) process. Therefore, understanding of PUREX process at the atomistic level using molecular dynamics simulations is of immense practical significance. Therefore, extensive molecular dynamics simulations have been conducted using calibrated all-atom optimized potentials. The simulation studies have been performed for a wide range of nitric acid concentration from 1 M to 8 M. MD studies reveal the importance of interfacial properties on the extraction of uranyl ions. The predicted interface thickness is seen to be increased with acidity whereas the calculated interfacial tension shows the opposite behavior. From the calculated results, it is observed that the capillary part of the total interface thickness is suppressed whereas the intrinsic part is expanded due to the packing of uranyl ions. The uranyl complexes remain adsorbed at the close proximity of the aqueous-organic interface. The predicted distribution constant of uranyl ion with increasing acidity exhibits a “curved profile“ as observed in the experiment. The computed interaction energy using DFT displays that the TiAP-UO22+ interaction energy is much higher compared to the TiAP-HNO3 and TiAP-H2O interaction energies thus support the higher distribution constant of uranyl ion. The high value of negative free energy difference, ΔΔG (ΔGSolvation - ΔGHydration) of uranyl ion in the organic and aqueous phase confirms that the partitioning of uranyl ion to the organic phase through complexation reaction is thermodynamically feasible process.

Induced fit, ensemble binding space docking and Monte Carlo simulations of MDMA ‘ecstasy’ and 3D pharmacophore design of MDMA derivatives on the human serotonin transporter (hSERT)

The popular recreational drug MDMA (3,4-methylenedioxy-methamphetamine) has a documented potential as a psychopharmacological clinical and research tool. This is due to its unique ability to promote reprocessing of traumatic memories, empathetic and pro-social states. Although it is established that MDMA exerts its behavioural effects via the serotonin transporter (SERT), the ligand-protein molecular interplay remains elusive. In order to shed light on the binding of MDMA and its primary congeneric entactogens (MDA, MBDB and MDAI), we first combined induced fit with Monte Carlo simulations. The computed interaction energies of the models correlated well with experimental activities (adjR2 = 0.78). Then we carried out ‘ensemble binding space docking’ on trajectories generated by interpolation of experimentally derived structures of the hSERT from the outward-open, and the occluded, to the inward-open states. This approach revealed low-energy alternative binding modes, suggesting high occupancy of the central site, yet considerable MDMA mobility within it, favouring the paroxetine-like orientation. Finally, we designed a pharmacophore that may be used to recognise hSERT-mediated serotonin releasers and uptake inhibitors of diverse chemical structure, identifying their active conformations and interacting residues. We conclude that the conserved amine-Asp98 ionic and edge-to-face π-π interactions are crucial to the mode of action of MDMA on the hSERT, underscoring the contributions of Tyr95 and gating residues Phe341, Tyr176 and Phe335. Amenable to experimental testing, our modelling may aid the rational design of novel entactogenic compounds and contribute to the understanding of an action mechanism, common and typical of psychotropic agents.

Influence of interface structure in redox and optical properties of thio and seleno-Ureidopeptide functionalized bimetallic gold nanocluster: DFT study

A simple cluster–ligand interaction model is introduced to describe the surface passivation of bimetallic gold clusters by SUP (Thioureidopeptide) and SeUP (Selenoureidopeptide) ligands. The conformational search based on neutral peptide binding modes and their computed interaction energies show the existence of various structural isomers within 10 kcal mol−1. Further, the negatively charged deprotonated peptide was found to strongly interact with metal cluster through the carboxylate unit. Irrespective of the mode of binding and configuration the metal cluster found to exist in parent geometry in all three charge states. The calculated HOMO-LUMO gap of ligated clusters predicts an increase in chemical stability after the ligation. Moreover, the ligation was found to decrease the energy required for oxidation and reduction. The excited-state calculations indicate absorption maxima at 200–400 nm corresponds to the LMCT transition. In all the hybrid cluster models the donor and acceptor end of the peptide were found to remain intact. However, the charge migration dynamics observed only in the homo-metallic gold-ligand hybrids, owing to the larger charge separation.

Rapid Ranking of Heterocycle-Side Chain Stacking Interactions Based on New Molecular Descriptors

Despite the importance of stacking interactions between ligands and aromatic amino acid side chains in binding sites, it is still unclear how such interactions can be optimized in the context of design. I will present highly-accurate computed interaction energies for parallel stacked dimers of aromatic amino acid side chains and pharmaceutically relevant heterocycles. The trends in binding energies that are observed can be described using a combination of known descriptors of dispersion and new electrostatic potential (ESP) based heterocycle descriptors we have developed which have been used to generate a multi-parameter predictive model for the interaction energy. These electrostatic descriptors are based on statistical features of the electric field and ESP in the plane near the heterocycle and can be directly related to the number and arrangement of the heteroatoms. This relationship provides a means for rapidly evaluating these descriptors, and consequently the stacking interaction energies, directly from simple molecular representations (e.g. SMILES, connectivity matrix). This enables the rapid ranking of large sets of heterocycles based on their stacking ability.

Corrosion Inhibition of Aluminium in Gas and Acid Media by Some Chalcone-Based N-(3-Aminopropyl)Imidazoles: TD-DFT-Based FMO, Conceptual DFT, QTAIM and EDA Studies

The efficacy and mode of action of five chalcone-based imidazole derivatives as corrosion inhibitors of aluminium metal in gas-phase and acidic medium have been investigated herein via quantum chemical calculations. Dispersion-corrected DFT (DFT-D3) and time-dependent DFT (TD-DFT) calculations were performed at PBE0/def2-TZVP//PBEh-3c and CAM-B3LYP/def2- TZVP levels of theory, respectively. Conceptual DFT, the quantum theory of atoms-in-molecules (QTAIM) and local energy decomposition (LED) analyses have been performed. The LED analysis was performed at the coupled-cluster singles and doubles with perturbative triples (CCSD(T))/def2-SVP level of theory. Frontier molecular orbital energy gaps calculated using the TD-DFT method are found to lie in the range 3.574 - 4.444 eV, indicative of good adsorption and corrosion inhibition efficacies of the investigated molecules. The interactions between aluminium and the inhibitor molecules studied are found to be energetically favorable, owing to negative computed interaction energy values. Furthermore, QTAIM analysis revealed metal-carbon, metal-oxygen and metal-nitrogen interactions in the inhibitor-aluminium complexes, which are predominantly electrostatic in character, according to LED analysis results. Calculated proton affinities (PAs) have revealed the anticorrosion potentials of the investigated inhibitors in acidic medium, with a noticeable dependency on temperature within the range 273.15 - 343.15 K.

Crystal and molecular structure stabilized by weak interaction in unique 3,5-diiodo-L-tyrosinato copper(II) complex – synthesis, experimental and theoretical studies

The ternary Cu(II)/amino-acid/diamine systems have large positive logK values than binary Cu/amino systems, suggesting stabilization due to the effective stacking interaction between aromatic diamine and the aromatic side group of the amino acid. Thus, a hybrid 3,5-diiodo-L−tyrosinato copper(II) complex with an aromatic diamine, of formula [Cu(L−I2TyrO-)(H2O)(phen)]∙2H2O (1) was characterized in depth by using X-ray, TG/DTG, DSC, FT-IR, Raman, Q-band EPR, NIR-Vis-UV, magnetic methods and the theoretical calculations. The crystal structure is stabilized by weak π···π stacking, metal···π and intra- and intermolecular π···I non-covalent interactions. The computed interaction energies of Cg(1)∙∙∙Cg(2), Cg(3)∙∙∙I and Cg(1)∙∙∙Cu ranging from 0.69 kcal/mol− -2.20 kcal/mol. The weak interactions shift the bands assigned as ν(C-I) to higher frequency in the FT-IR spectrum. The g tensor is axial with g|| (2.239) > g⊥ (2.057) indicating that the unpaired electron residues in the dx2–y2 orbital. The exchange pathway occurs in the zig-zag chain with d(Cu···Cu) = 9.429 Å.

A statistically guided grid generation method and its application to intermolecular potential energy surfaces.

We present a method for the generation of points in space needed to create training data for fitting of nonlinear parametric models. This method uses statistical information extracted from an initial fit on a sparse grid to select optimal grid points in an iterative manner and is, therefore, called the iterative variance minimizing grid approach. We demonstrate the method in the case of six-dimensional intermolecular potential energy surfaces (PESs) fitted to ab initio computed interaction energies. The number of required grid points is reduced by roughly a factor of two in comparison to alternative systematic sampling methods. The method is not limited to fitting PESs and can be applied to any cases of fitting parametric models where data points may be chosen freely but are expensive to obtain.

Radiation-Induced Transformation of CHF3···CO to the CF3···CO Complex: Matrix Isolation and Ab Initio Study.

The X-ray-induced transformations of CHF3/CO/Ar and CHF3/CO/Kr systems were investigated by Fourier transform infrared (FTIR) matrix isolation spectroscopy at 6 K. It was found that addition of CO suppressed decomposition of fluoroform in an Ar matrix, probably because of trapping of matrix holes by CO and CHF3···CO complexes. Considerable increase of the CF3/CF2 ratio with increasing CO content in the matrix was attributed to stabilization of the CF3 radical with respect to further radiation-induced fragmentation because of its complexation with the CO molecule. The CF3···CO complex generated from the CHF3···CO precursor complex was characterized by FTIR spectroscopy and ab initio calculations at the CCSD(T) and MP2 levels of theory. To the best of our knowledge, it is the first experimentally observed complex of the CF3 radical. The computed interaction energy was found to be 0.35 kcal/mol at the CCSD(T)/L2a_3 level (0.36 kcal/mol at the MP2/L2a_3 level), taking into account zero-point energy and basis set superposition error corrections. Despite the very weak intermolecular bonding, the complex is characterized by distinct features in the regions of C-F symmetric and antisymmetric stretching (CF3) and CO stretching (the latter one was observed only in a krypton matrix). The geometrical structure of the radical-molecule complex is close to that of its molecular precursor.

Electrostatics and Polarization in σ- and π-Hole Noncovalent Interactions: An Overview.

The energetics of σ- and π-hole interactions can be described very well in terms of electrostatics and polarization, consistent with their Coulombic natures. When both of these components are taken into account, very good correlations with quantum-chemically computed interaction energies are obtained. If polarization is only minor, as when the interactions are quite weak, then electrostatics can suffice, as represented by the most positive electrostatic potential associated with the σ- or π-hole. For stronger interactions, the combination of electrostatics plus polarization is very effective even for interaction energies considerably greater in magnitude than what is normally considered noncovalent bonding. Several procedures for treating polarization are summarized, including the use of point charges and the direct inclusion of electric fields.

Nonlocal Subsystem Density Functional Theory.

By invoking a divide-and-conquer strategy, subsystem DFT dramatically reduces the computational cost of large-scale, ab initio electronic structure simulations of molecules and materials. The central ingredient setting subsystem DFT apart from Kohn-Sham DFT is the nonadditive kinetic energy functional (NAKE). Currently employed NAKEs are at most semilocal (i.e., they only depend on the electron density and its gradient), and as a result of this approximation, so far large-scale simulations only included systems composed of weakly interacting subsystems. In this work, we advance the state-of-the-art by introducing fully nonlocal NAKEs in subsystem DFT simulations for the first time. A benchmark analysis based on the S22-5 test set shows that nonlocal NAKEs considerably improve the computed interaction energies and electron densities compared to commonly employed GGA NAKEs, especially when increasing intersubsystem electron density overlap is considered. Most importantly, we resolve the long-standing problem of too attractive interaction energy curves typically resulting from the use of GGA NAKEs.

GroScore: Accurate Scoring of Protein-Protein Binding Poses Using Explicit-Solvent Free-Energy Calculations.

Protein-protein docking algorithms promise a potential relief for the mismatch between the number of experimentally determined complex structures and the number of relevant protein interactions in an organism. To distinguish correctly from wrongly generated poses, it is necessary to score complexes according to their structural similarity to the real complex, which is usually done by computing interaction energies of some sort. Here, we explore the potential of free-energy calculations with statistical-mechanical foundation in the context of molecular dynamics (MD) simulations with explicit solvent to score a large number of complex poses. We introduce an adaptive sampling scheme which ensures that most sampling time is spent on the most promising poses. Our approach is illustrated by scoring of all targets in the CAPRI Score_set, a scoring benchmark set, and three additional CAPRI targets, together consisting of more than 22 000 poses. Our scoring scheme shows a performance that is competitive with the most successful approaches that were previously reported. All necessary scripts to run the automated scoring pipeline are available in the Supporting Information for this paper.