Semiempirical Method PM7 Research Articles

Electrochemical and theoretical studies of the interaction between anticancer drug ponatinib and dsDNA

In this study, electrochemical and theoretical studies were performed to explain the interaction mechanism between ponatinib (PNT), a third generation tyrosine kinase inhibitor, and dsDNA. The electrochemical part was conducted in phosphate-buffered saline (PBS) at physiological pH of 7.4 and in acetate buffer with a pH of 4.7, using square wave voltammetry. A boron-doped diamond electrode was used in a bulk-incubated solution. The theoretical part was investigated using computational methods, such as the semiempirical method PM7 and density functional theory (DFT). Significant differences in the electrochemical behavior of PNT in the presence of DNA confirmed the occurrence of interactions. The results obtained in the acetate buffer strongly suggested the preferential interaction of PNT with guanine residues. However, at physiological pH, it can be concluded that PNT interacts with dGua and dAdo in the dsDNA molecule. These results are consistent with outcomes from the theoretical studies, where quantum-chemical calculations showed that both electrochemically detectable nucleobases form hydrogen bonds with the drug. These bonds appeared to be stronger with guanine than with adenine. According to the computational studies, the dsDNA major groove is the energetically preferred site for the complexation of PNT.

The Use of Factorial Planning in the Investigation of Structural Electronics Property for the Rational Design of Benzophenone Derivatives

Human exposure to ultraviolet (UV) radiation leads photochemical excitation processes in the skin, causing problems to human health. The use of photoprotectors helps to minimize these intrinsic hazards. Benzophenone molecules stand out for the absorption of energy in the UVA and UVB range and structural changes in these, it is an area of ​​interest to obtain safer and more effective molecules. This work applied the full factorial design methodology 24 in an investigation by molecular modeling using semi-empirical method PM7, in order to evaluate the impact generated on the decrease of the energy GAP with the insertion of OH (level +) and H (level –-). The results showed unfavorable and favorable contributions between interactions and in the main effect, and the compounds disubstituted in ortho and para position for the same aromatic ring showed a better percentage of contribution, indicating that these conditions are relevant for greater reactivity compared to the others. Thus, we conclude that the use of the experimental planning methodology is an ally in obtaining information for planning new protective filtersmore stable and safe.

Solvation Free Energies for Aqueous and Nonaqueous Solutions Computed Using PM7 Atomic Charges

We describe a simple and accurate method, ESE-PM7, for calculating solvation free energies ΔGsolv° in aqueous and nonaqueous solutions. The method is based on a noniterative COSMO algorithm. Molecular geometries and atomic charges calculated using the semiempirical method PM7 are used to calculate ΔGsolv°. The method has been tested on 92 different solvents and 988 solutes. The mean absolute errors (MAEs) in ΔGsolv° in aqueous solutions estimated by the ESE-PM7 approach are found to be 1.62 kcal/mol for 389 neutral solutes and 3.06 kcal/mol for 139 ions. The MAEs for neutral molecules in organic solvents are 0.97, 0.74, and 0.51 kcal/mol in polar protic, polar aprotic, and nonpolar solvents, respectively. The developed method can be employed to quickly screen ΔGsolv° values of extended molecular systems including pharmaceutical and biological molecules.

USING QUANTUM-CHEMICAL PARAMETERS FOR PREDICTING ANTIRADICAL (HO•) ACTIVITY OF RELATED STRUCTURES CONTAINING A CINNAMOIL FRAGMENT. IV. STRUCTURE-ACTIVITY RELATIONSHIP BETWEEN UNSATURATION INDICES AND FLAVONE DERIVATIVES WITH FLOROGLUCIN RING “A”

The quantum-chemical parameters of 52 derivatives related to flavanones, flavanonoles, flavones and flavonoles with a phloroglucinic type of the A ring and containing electron-donating substituents in the B ring were studied.The aim is the analysis of the dynamics of changes in the electron density, bond numbers, free valence indices and unsaturation indices on carbon atoms C-7 → C-8 of the vinyl group of the main conjugation chain in relation to the position and number of substituents in the “B” ring and the type of the pharmacological activity.Materials and methods. The quantum-chemical parameters of the 4 analyzed groups of the compounds, have been calculated by the semi-empirical method PM7 (WinMopac 2016 program) on the workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results and discussion. When comparing the quantum chemical parameters of the analyzed compounds, it was established that when the C-7 → C-8 multiple bond is formed, the free valency and unsaturation indices increase on both carbon atoms of the vinylene group in flavones and flavonols compared to the corresponding flavanones and flavanonols. This is explained by the fact that the value of the bond numbers Nµ on these atoms, on the contrary, decreases (Fµ = 4.732-Nµ). The transition from flavanone to flavone is accompanied by the formation of a vinyl group C-7 → C-8, and therefore both atoms from the sp3-hybridized state go into the sp2-state. The consequence of this transformation is a change in the electronegativity value and an increase in the unsaturation index of C-7 and C-8 atoms: C sp3 = 2.5; Csp2 = 2.8. At the same time, the transition from flavanone to flavone leads to the formation of a conjugated system with the participation of π-electrons of the aromatic system “B”, C-7, C-8 atoms and the carbonyl group, which is commonly called the “main conjugation chain”. These structural changes, namely, the transition from a less oxidized flavanone to a more oxidized flavone, contribute to a decrease in the electron density on C-7 and C-8 atoms, and an increase in the total unsaturation of the molecules in general. Mulliken charges on C-7 of all groups of compounds are characterized by a positive value. As for the carbon atoms of the B fragment, the following features are revealed here: in the presence of one substituent -OH or -OCH3 on the carbon atom to which the substituent is bounded, the Mulliken charge is positive; if there are two substituents in the B ring -OH or -OCH3, as well as two -OCH3 groups, then the carbon atoms bonded to the indicated substituents also have a positive Mulliken charge; in the case of trihydroxy substituted in the C-2, C-3 and C-4 B ring, all three carbon atoms are characterized by a positive Mulliken charge; if there are methoxy groups in positions C-2, C-3 and C-4, then the positive Mulliken charge is concentrated only on C-2 and C-4 atoms, and on C-3 atom this charge has a negative value.Conclusion. The above data on the quantum-chemical parameters of the main conjugation chain indicate that the transition of C-7 and C-8 atoms to the sp2-hybrid state, leads to a decrease in the electron density and a decrease in the bond numbers, with a simultaneous increase in the indices of unsaturation and free valence on these atoms. Thus, the trigger mechanism of the anti-radical activity, primarily with respect to the HO • radical, is determined by the fact that this particle, electrophilic in its properties, will attach in the C-8 atom during an initial attack.

THEORETICAL INVESTIGATION OF CHARGE TRASFER EFFECT IN 3-METHYLTHIO-4-PHENYL-5-PHENYLAMINO-1,2,4-TRIAZOL-1-IUM HEXABROMOTELLURATE

Hexabromotellurates of some heterocyclic organic bases exhibit semiconductor properties. Promising photoelectric properties are demonstrated by a number of hexaiodotellurate-containing defect perovskites. The study of hybrid organic-inorganic compounds is an urgent task of modern science, as such new functional materials can be used as effective converters of solar energy. In our previous works, a method for the synthesis of hexabromotellurate of 3-methylthio-4-phenyl-5-phenylamino-1,2,4-triazol-1-ium A+ was developed and its main photoelectric properties were theoretically investigated. In this work, it was decided to continue the study of the properties of this hexabromotellurate, and the use of quantum chemical methods allowed it to investigate the effect of charge transfer between the hexabromotellurate anion and the organic cation A+.
 Geometry optimization of the [A-TeBr6]– with the charge of –1 was performed by the semiempirical method PM7 in the program MOPAC2016 and by the DFT method PBE/λ1 in the program PRIRODA 19. The charge transfer effect was investigated based on the electron density generated by the ωB97X-D3/def2-SVP method in ORCA 4.2.1. The effects of the medium (gas phase, chloroform, tetrahydrofuran, n-octanol, acetone, acetonitrile, water) were taken into account using the CPCM model. The Multiwfn 3.8 package was used to analyze the electron density.
 From the analysis of the isosurface of the electrostatic potential, carried out by using the "charge decomposition analysis" method, and also from the analysis of the total charges of the fragments A+ and TeBr62–, it has been found that in the [A-TeBr6]– associate a great charge transfer from the anion to the organic cation is present. The complex orbitals HOMO and HOMO–1 in the [A-TeBr6]– associate correspond to the cation's HOMO and the anion's HOMO, respectively. These two orbitals generally remain undisturbed during the formation of the complex. It has been established that with the medium's dielectric constant increase, the number of electrons transferred from the anion to the cation decreases markedly, which is consistent with Coulomb's law. It is noted that even in the case of non-polar solvents, this kind of calculations must take into account the dielectric constant of the medium.

Encapsulation of Pollutant Gaseous Molecules by Adsorption on Boron Nitride Nanotubes: A Quantum Chemistry Study

Based on density functional theory (DFT) and the semiempirical method PM7, we analyze the encapsulation process of polluting gases and/or their adsorption on different sites, viz., on the inner wall, the outer wall, and on the boron nitride (BN) nanotube ends, with chirality (7,7) armchair. DFT calculations are performed using the Perdew–Burke–Ernzerhof (PBE) functional and the M06-2X method through the 6-31G(d) divided valence orbitals as an atomic basis. Various geometrical configurations were optimized by minimizing the total energy for all analyzed systems, including the calculation of vibrational frequencies, which were assumed to be of a nonmagnetic nature, and where the total charge was kept neutral. Results are interpreted in terms of adsorption energy and electronic force, as well as on the analysis of quantum molecular descriptors for all systems considered. The study of six molecules, namely, CCl4, CS2, CO2, CH4, C4H10, and C6H12, in gas phase is addressed. Our results show that C4H10, C6H12, and CCl4 are chemisorbed on the inner surfaces (encapsulation) and on the nanotube ends. In contrast, the other molecules CS2, CO2, and CH4 show weak interaction with the nanotube surface, leading thereby to physisorption. Our findings thus suggest that this kind of polluting gases can be transported within nanotubes by encapsulation.

USE OF QUANTUM-CHEMICAL PARAMETERS FOR FORECASTING ANTIRADICAL (HO·) ACTIVITY OF RELATED STRUCTURES CONTAINING A CINNAMIC MOLD FRAGMENT. III. CHALCONES, FLAVANONES AND FLAVONES WITH PHLOROGLUCINIC TYPE OF RING “A”

42 derivatives of chalcone, flavanone and flavone having a phloroglucinic type of ring “A” and containing the same electron-donating substituents on ring “B”, have been studied. Flavonoids with the phloroglucinic type of ring “A” are the most common in nature, which is due to the peculiarities of biogenetic formation with the participation of malonyl and acetyl fragments.The aimof the article isto determine the effect of the hydroxy group in position 6' of chalcones and in position 5 of flavanones and flavones on bond numbers (Nµ), free valence indices (Fµ), Mulliken charges (a.e), electron density, unsaturation indices (IUA) of the carbon atoms C-1 → C-6 → C-7 → C-8.Materials and methods. The calculations of the listed above parameters with the use of the semi-empirical method PM7 (WinMopac 2016 program) have been carried out on a workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results.The quantum-chemical characteristics of the considered derivatives having a phloroglucinic type of the “A” ring, indicate that the OH group in position 6' of chalcones (in the corresponding flavanones and flavones in position 5) has different effects: a slight increase occurs in chalcones negative charge (a.e.) and electron density, the bond numbers take different values, which depends on the position and number of substituents on the ring "B". In flavanones, Nµ practically remains at the same level of 3.822-3.829. For flavones, the binding numbers Nµ for C-8 are in the range of 3.700-3.706, and the Mulliken charges are in the range from -0.4120 to -0.4356. For position-substituted C-3 (6anone and 7anone), the charges are -0.4436 and -0.4479, respectively. The charge on C-7 of chalcones is negative for compounds 4x, 5x, 10x and 13x from -0.0204 to -0.0470. The remaining derivatives of the chalcone, as well as the corresponding flavanones and flavones, are characterized by a positive value of a.e. on C-7. Based on the bond numbers (Nµ), free valency indices (Fµ) have been found for the carbon atoms of the cinnamoyl fragment C-1 → C-6 → C-7 → C-8. When comparing the obtained data, it was found out that for chalcones on C-1 → C-8 atoms, the values of the free valence indices are in the range of 0.900-0.980 for compounds 12x, 13x, where Fµ> 1. For flavanones on C-1, C-3, and C-5 atoms (compounds 12anone and 13anone), the free valence indices are in the range of 0.984-1.024, and for the remaining atoms the value of Fµ is approximately the same as that of chalcones. On the C-8 atoms of all the derivatives, as well as on C-1, C-3 and C-5 (compounds 12one, 13one), Fµ ≥ 1.0. It can be assumed that at values of Fµ = 0.850-0.955 for all the analyzed compounds, coupling reactions on the double bond are possible, and if Fµ ≥1, the coupling will take place according to the free radical mechanism. The data obtained indicate that the OH group in position 6’ for the chalcone and 5 for the flavanones, does not significantly effect the Mulliken charge (a.e) and the electron density on C-8 atoms.Conclusion.It has been established that the OH group in position 6' of the "A" ring of chalcones (in position 5 of the "A" ring in flavones and flavanones) has a conflicting effect on the bond numbers: when passing from chalcone to flavanone, Nµ increases, and then, in flavone, sharply decreases. For C-8 of all flavone derivatives, Fµ ≥1. The following conclusion has been confirmed: at the initial stage of the reaction the electrophilic hydroxyl radical is attached at the C-8 position of the cinnamoyl fragment

USING QUANTUM-CHEMICAL PARAMETERS FOR PREDICTING ANTI-RADICAL (НО∙) ACTIVITY OF RELATED STRUCTURES CONTAINING A CINNAMOYL FRAGMENT II. DERIVATIVES OF 2’,4’-DIHYDROXYCHALCONE, FLAVANONE AND FLAVONE, CONTAINING A HYDROXY GROUP IN POSITION 7

42 derivatives of 2’,4’-dihydroxychalcone, flavanone and flavone, containing the hydroxy group in position 7 (ring "A"), as well as substituents in the ring "B", have been studied.The aim is to study the quantum-chemical parameters of 2',4'-dihydroxychalcone, flavanone and flavone derivatives containing a hydroxy group in position 7, in order to identify the effect of substituents on Mulliken charges (a.e) in the aromatic core "A", bond numbers (Nµ), the unsaturation index (IUA) and the electron density of the carbon atoms of the cinnamoyl fragment.Materials and methods. The listed above parameters have been calculated by the semi-empirical method PM7 (WinMopac 2016 program) on the workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.Results. The analysis of the values of quantum-chemical parameters, as well as their comparison with the corresponding indicators presented in Report I, revealed a number of important features associated with the influence of the hydroxy group in position 7 (ring "A") on the studied quantum-chemical parameters of molecules. It has been established that the hydroxy group in the ring “A” does not significantly affect the Mulliken charge and the electron density of the carbon atoms of the propenone unit C-7→C-8→C-9. On atom C-9 (carbonyl carbon), the Mulliken charge always has a positive value, and the electron density is about 3.4670-3.4840 for all three groups of compounds. The transition from 2’,4’-dihydroxychalcone to flavanone and flavone by the formation of the pyrone heterocycle, is accompanied by an increase in the negative charge on C-8, which can be explained by the involvement of the oxygen heteroatom in the transmission of electronic effects. The hydroxy group in the ring “A”, has practically no effect on the charge and electron density of atoms. An analysis of the values of bond numbers and unsaturation indices suggests that atoms C-1 of 2’,4’-dihydroxychalcone and 7-hydroxyflavanone derivatives, are characterized by the lowest Nµ value; the lowest bond numbers are characteristic for atom C-8 derivatives of 7-hydroxyflavone. Consequently, the primary attack of the HO·radical will be directed at C-1 (in chalcones and flavanones) and at C-8 in flavones.Conclusion. The performed quantum-chemical calculations make it possible to analyze the effect on the main quantum-chemical parameters of the molecule, which can be useful in predicting the biological activity of flavanoid compounds due to their antiradical effect on reactive oxygen intermediate species (ROIs).

A procedure combining molecular docking and semiempirical method PM7 for identification of selective Shp2 inhibitors

Shp2 and Shp1 make up a small family of protein tyrosine phosphatases. Finding selective inhibitors for Shp2 is useful because although its inhibition is advantageous for the treatment of some types of cancer, inhibition of Shp1 may have the opposite effect, since it acts as a suppressor of tumors. We combined molecular docking and semiempirical molecular orbital-based calculations to produce data that were effective for the identification of selective inhibitors for Shp2. After definition of the interaction modes of the inhibitors with Shp2 and Shp1 by molecular docking, the resulting interaction enthalpy values were calculated following refinement of the enzyme/inhibitor complexes' geometries with the PM7 semiempirical molecular orbital method. Despite the complexity of the thermodynamics involved in the enzyme/inhibitor interaction, the selectivity for Shp2 of a series of 76 inhibitors, divided in two groups, could be effectively correlated with the difference in their interaction enthalpy values with both enzymes. For the first group, composed by 52 Shp2-selective indoline inhibitors for which only Shp2 inhibition activity data are available, we demonstrated that the interaction enthalpy can be used as a criterion for identification of selective Shp2 inhibitors, as it is significantly more favorable for Shp2 than Shp1 at a 99% confidence level. For the second group, composed by 24 oxindole derivatives with available Shp2 and Shp1 inhibition activity data, a satisfactory correlation (R = 0.70) could be obtained between the selectivity, based on the IC50 data, and the relative percentage difference of the calculated interaction enthalpies with the two enzymes.

USING QUANTUM-CHEMICAL PARAMETERS FOR PREDICTING ANTI-RADICAL (НО∙) ACTIVITY OF RELATED STRUCTURES CONTAINING A CINNAMIC MOLD FRAGMENT. I. DERIVATIVES OF CINNAMIC ACID, CHALCON AND FLAVANON

45 compounds uniting 3 groups of derivatives of cinnamic acid, chalcone and flavanone, have been studied. Each of them includes 15 substances. The analyzed compounds contain a common structural fragment, which is a cinnamic acid residue (cinnamoyl fragment).The aimis to study the quantum-chemical parameters of the listed groups of the compounds in order to predict possible ways of their interaction with the most aggressive and dangerous of the active oxygen species (ROS) – a hydroxyl radical.Materials and methods.For the analyzed structures, the Mulliken charges (a.u.), bond numbers (Nμ), unsaturation index (IUA), and electron density values on all 9-carbon atoms of the cinnamoyl fragment have been determined. The calculations have been carried out on a workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM. The semi-empirical method PM7 was used (WinMopac 2016 program). The ORCA 4.1 program was used to calculate the energies of homolytic cleavage of the O – H bond.Results.The analysis of Mulliken charges (a.u.), bonded numbers (Nμ), unsaturation indices (IUA), and electron density revealed a number of regularities on the basis of which it can be concluded, that taking into account the nature of the substituent, the most probable for addition in the aryl residueare positions C-1, C-2, C-3, C-4 and C-5. In the propenone fragment, the radical НО∙ first attacks position 8, then 7. For the hydroxy-substituted, the energy of the homolytic breaking of the H – O bond has been determined and it has been established that the spatial difficulty of phenols (compounds 13k, 13x, 13f, 14k, 14x, 14f) H-O bonds are the smallest and on average are -160.63 kJ/mol. It has also been established that the higher the positive Mulliken charge on the carbon atom with which the phenolic hydroxyl is bound, the lower the energy of the homolytic breaking of the H – O bond and the more stable the resulting phenoxy radicalis.Conclusion.The carried out quantum chemical calculations allow us to conclude that the studied classes of compounds can be used to bind the hydroxyl radical formed in the body, causing various kinds of mutations, leading, among other things, to the development of oncological diseases.

An investigation into the applicability of the semiempirical method PM7 for modeling the catalytic mechanism in the enzyme chymotrypsin

The catalytic cycle for the serine protease α-chymotrypsin was investigated in an attempt to determine the suitability of using the semiempirical method PM7 in the program MOPAC for investigating enzyme-catalyzed reactions. All six classical intermediates were modeled using standard methods, and were characterized as stable minima on the potential energy surface. Using a modified saddle point optimization method, five transition states were located and verified both by vibrational and by intrinsic reaction coordinate analysis. Some individual features, such as the hydrogen bonds in the oxyanion hole, the nature of various electrostatic interactions, and the role of Met192, were examined. This involved designing and running computational experiments to model mutations that would allow features of interest, in particular the energies involved, to be isolated. Three features within the enzyme were examined in detail: the reaction site itself, where covalent bonds were made and broken, the electrostatic effects of the buried aspartate anion, a passive but essential component of the catalytic triad, and the oxyanion hole, where hydrogen bonds help stabilize charged intermediates. With one minor exception, all phenomena investigated agreed with previously-reported descriptions. This result, along with the fact that all the techniques used were relatively straightforward, leads to the recommendation that PM7 and related methods, such as PM6-D3H4, are appropriate for modeling similar enzyme-catalyzed reactions.Graphical abstractFifth of six transition states, showing water splitting into hydroxyl anion and a proton, to form the second tetrahedral intermediate and histidinium ion. Atoms of the water molecule involved in the hydrolysis are indicated by halos.

Octopus: a platform for the virtual high-throughput screening of a pool of compounds against a set of molecular targets.

Octopus is an automated workflow management tool that is scalable for virtual high-throughput screening (vHTS). It integrates MOPAC2016, MGLTools, PyMOL, and AutoDock Vina. In contrast to other platforms, Octopus can perform docking simulations of an unlimited number of compounds into a set of molecular targets. After generating the ligands in a drawing package in the Protein Data Bank (PDB) format, Octopus can carry out geometry refinement using the semi-empirical method PM7 implemented in MOPAC2016. Docking simulations can be performed using AutoDock Vina and can utilize the Our Own Molecular Targets (OOMT) databank. Finally, the proposed software compiles the best binding energies into a standard table. Here, we describe two successful case studies that were verified by biological assay. In the first case study, the vHTS process was carried out for 22 (phenylamino)urea derivatives. The vHTS process identified a metalloprotease with the PDB code 1GKC as a molecular target for derivative LE&007. In a biological assay, compound LE&007 was found to inhibit 80% of the activity of this enzyme. In the second case study, compound Tx001 was submitted to the Octopus routine, and the results suggested that Plasmodium falciparum ATP6 (PfATP6) as a molecular target for this compound. Following an antimalarial assay, Tx001 was found to have an inhibitory concentration (IC50) of 8.2μM against PfATP6. These successful examples illustrate the utility of this software for finding appropriate molecular targets for compounds. Hits can then be identified and optimized as new antineoplastic and antimalarial drugs. Finally, Octopus has a friendly Linux-based user interface, and is available at www.drugdiscovery.com.br . Graphical Abstract Octopus: A platform for inverse virtual screening (IVS) to search new molecular targets for drugs.

A method for predicting individual residue contributions to enzyme specificity and binding-site energies, and its application to MTH1.

A new method for predicting the energy contributions to substrate binding and to specificity has been developed. Conventional global optimization methods do not permit the subtle effects responsible for these properties to be modeled with sufficient precision to allow confidence to be placed in the results, but by making simple alterations to the model, the precisions of the various energies involved can be improved from about ±2 kcal mol−1 to ±0.1 kcal mol−1. This technique was applied to the oxidized nucleotide pyrophosphohydrolase enzyme MTH1. MTH1 is unusual in that the binding and reaction sites are well separated—an advantage from a computational chemistry perspective, as it allows the energetics involved in docking to be modeled without the need to consider any issues relating to reaction mechanisms. In this study, two types of energy terms were investigated: the noncovalent interactions between the binding site and the substrate, and those responsible for discriminating between the oxidized nucleotide 8-oxo-dGTP and the normal dGTP. Both of these were investigated using the semiempirical method PM7 in the program MOPAC. The contributions of the individual residues to both the binding energy and the specificity of MTH1 were calculated by simulating the effect of mutations. Where comparisons were possible, all calculated results were in agreement with experimental observations. This technique provides fresh insight into the binding mechanism that enzymes use for discriminating between possible substrates.

Accuracy issues involved in modeling in vivo protein structures using PM 7

ABSTRACTUsing the semiempirical method PM7, an attempt has been made to quantify the error in prediction of the in vivo structure of proteins relative to X‐ray structures. Three important contributory factors are the experimental limitations of X‐ray structures, the difference between the crystal and solution environments, and the errors due to PM7. The geometries of 19 proteins from the Protein Data Bank that had small R values, that is, high accuracy structures, were optimized and the resulting drop in heat of formation was calculated. Analysis of the changes showed that about 10% of this decrease in heat of formation was caused by faults in PM7, the balance being attributable to the X‐ray structure and the difference between the crystal and solution environments. A previously unknown fault in PM7 was revealed during tests to validate the geometries generated using PM7. Clashscores generated by the Molprobity molecular mechanics structure validation program showed that PM7 was predicting unrealistically close contacts between nonbonding atoms in regions where the local geometry is dominated by very weak noncovalent interactions. The origin of this fault was traced to an underestimation of the core‐core repulsion between atoms at distances smaller than the equilibrium distance. Proteins 2015; 83:1427–1435. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

On the performance of the semiempirical quantum mechanical PM6 and PM7 methods for noncovalent interactions

In this Letter, we compare the recently released semiempirical method PM7 with its predecessor, PM6 with post-SCF corrections. These corrections were introduced in order to improve the description of noncovalent interactions (dispersion, hydrogen bonds and halogen bonds) and have become an integral part of PM7. A large collection of data on noncovalent interactions, covering not only interaction energies but also conformational changes and geometries, is used as a benchmark. Among the methods tested, PM6 with the latest corrections (PM6-D3H4X) yields the best results. PM7 yields only slightly worse results but brings additional improvements in the description of other molecular properties.