Molecular interactions between estrogen receptor and its ligand studied by the ab initio fragment molecular orbital method

The ab initio fragment molecular orbital calculations were performed for molecular interactions of the whole estrogen receptor (ER) ligand-binding domain with a natural ligand, 17beta-estradiol (EST). The interaction energies of the ligand at the residue level were calculated using HF and MP2 methods with several basis sets. The charge-transfer (CT) interactions were also analyzed based on configuration analysis for fragment interaction. Strong electrostatic interactions were observed between the EST and surrounding charged/polarized residues, Glu353, Arg394, His524, and Thr347. Weak electrostatic and significant van der Waals dispersion interactions were observed between the EST and the many surrounding hydrophobic residues. Together with the experimental interpretations, both interactions equally contributed to the total binding energies, and it was found that the inclusion of electron correlation was essential to obtain an appropriate picture of the interaction. The strongest interaction energy was observed between Glu353 and the EST, and the CT interactions from the lone-pair orbital of the carbonyl oxygen of Glu353 to the sigma(OmicronEta) orbital of the hydroxyl group of EST were found to be important. The CT interactions from the lone-pair orbital of EST to the sigma(NuEta) of Arg394 and from the lone-pair orbital of EST to the sigma(NuEta) of His524 were also observed. These CT interactions occurred through the hydrogen-bond networks between the ER and EST. Therefore, electron donations from the ER to the EST and electron back-donations from EST to the ER were characteristic of ER-ligand binding. Our approach provides a powerful tool to understanding detailed molecular interactions at the quantum mechanical level.     

Aggregation mechanism of polyglutamine diseases revealed using quantum chemical calculations, fragment molecular orbital calculations, molecular dynamics simulations, and binding free energy calculations

Polyglutamine (polyQ) diseases, including Huntington’s disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. The aggregation mechanism of polyQ diseases, the inhibition mechanism of Congo red, and the alleviation mechanism of trehalose were proposed here based on quantum chemical calculations and molecular dynamics simulations. The calculations and simulations revealed the following. The effective molecular bonding is between glutamine (Gln) and Gln (Gln + Gln), between Gln and Congo red (Gln + Congo red), and between Gln and trehalose (Gln + trehalose). The bonding strength is −13.1 kcal/mol for Gln + Gln, −24.4 kcal/mol for Gln + Congo red, and −12.0 kcal/mol for Gln + trehalose. In the polyQ region, both the number of intermolecular Gln + Gln formations and the total calories generated by the Gln + Gln formation are proportional to the number of repetitions of Gln. We propose an aggregation mechanism whose heat generated by the intermolecular Gln + Gln formation causes the pathogeny of polyQ disease. In our aggregation mechanism, this generated heat collapses the host protein and promotes fibrillogenesis. Without contradiction, our mechanism can explain all the experimental results reported to date. Our mechanism can also explain the inhibition mechanism by Congo red as an inhibitor of polyglutamine-induced protein aggregation and the alleviation mechanism by trehalose as an alleviator of that aggregation. The inhibition mechanism by Congo red is explained by the strong interaction with Gln and by the characteristic structure of Congo red.     

Higher-order correlated calculations based on fragment molecular orbital scheme

We have developed a new module for higher-order correlated methods up to coupled-cluster singles and doubles with perturbative triples (CCSD(T)). The matrix-matrix operations through the DGEMM routine were pursued for a number of contractions. This code was then incorporated into the ABINIT-MPX program for the fragment molecular orbital (FMO) calculations. Intra-fragment processings were parallelized with OpenMP in a node-wise fashion, whereas the message passing interface (MPI) was used for the fragment-wise parallelization over nodes. Our new implementation made the FMO-based higher-order calculations applicable to realistic proteins. We have performed several benchmark tests on the Earth Simulator (ES2), a massively parallel computer. For example, the FMO-CCSD(T)/6-31G job for the HIV-1 protease (198 amino acid residues)?Clopinavir complex was completed in 9.8?h with 512 processors (or 64 nodes). Another example was the influenza neuraminidase (386 residues) with oseltamivir calculated at the full fourth-order M?ller?CPlesset perturbation level (MP4), of which job timing was 10.3?h with 1024 processors. The applicability of the methods to commodity cluster computers was tested as well.     

Antigen�Cantibody interactions of influenza virus hemagglutinin revealed by the fragment molecular orbital calculation

Effective interactions between amino acid residues in antigen?Cantibody complex of influenza virus hemagglutinin (HA) protein can be evaluated in terms of the inter-fragment interaction energy (IFIE) analysis with the fragment molecular orbital (FMO) method, in which each fragment contains the side chain of corresponding amino acid residue. We have carried out the FMO-MP2 (second-order Moeller?CPlesset) calculation for the complex of HA antigen and Fab antibody of influenza virus H3N2 A/Aichi/2/68 and obtained the IFIE values between each amino acid residue in HA and the whole antibody as the sums over the residues contained in the latter. Combining this IFIE data with experimental data for hemadsorption activity of HA mutants, we succeeded in theoretically explaining the mutations in HA observed after the emergence of influenza virus H3N2 A/Aichi/2/68 in an earlier study, except for those of THR83. In the present study, we employ an alternative way of fragment division in the FMO calculation at the carbonyl C site of the peptide bond instead of the C_?? site used in the previous work, which provides revised IFIE values consistent with all the historical mutation data in the antigenic region E of HA including the case of THR83 in the present prediction scheme for probable mutations in HA.     

Intra- and intermolecular interactions between cyclic-AMP receptor protein and DNA: ab initio fragment molecular orbital study

The ab initio fragment molecular orbital (FMO) calculations were performed for the cAMP receptor protein (CRP) complexed with a cAMP and DNA duplex to elucidate their sequence-specific binding and the stability of the DNA duplex, as determined by analysis of their inter- and intramolecular interactions. Calculations were performed with the AMBER94 force field and at the HF and MP2 levels with several basis sets. The interfragment interaction energies (IFIEs) were analyzed for interactions of CRP-cAMP with each base pair, DNA duplex with each amino acid residue, and each base pair with each residue. In addition, base-base interactions were analyzed including hydrogen bonding and stacking of DNA. In the interaction between DNA and CRP-cAMP, there was a significant charge transfer (CT) from the DNA to CRP, and this CT interaction played an important role as well as the electrostatic interactions. It is necessary to apply a quantum mechanical approach beyond the "classical" force-field approach to describe the sequence specificity. In the DNA intramolecular interaction, the dispersion interactions dominated the stabilization of the base-pair stacking interactions. Strong, attractive 1,2-stacking interactions and weak, repulsive 1,3-stacking interactions were observed. Comparison of the intramolecular interactions of free and complexed DNA revealed that the base-pairing interactions were stronger, and the stacking interactions were weaker, in the complexed structure. Therefore, the DNA duplex stability appears to change due to both the electrostatic and the CT interactions that take place under conditions of DNA-CRP binding.     

Parallelized integral-direct CIS(D) calculations with multilayer fragment molecular orbital scheme

We have developed a parallelized integral-direct code of the perturbative doubles correction for configuration interaction with singles, proposed as CIS(D) by Head-Gordon et al. (Chem Phys Lett 219:21, 1994). The CIS(D) method provides the energy corrections both of the relaxation and differential correlation for the respective CIS excited states. The implementation of CIS(D) is based on our original algorithm for the second-order Møller–Plesset perturbation (MP2) calculations (Mochizuki et al. in Theor Chem Acc 112:442, 2004). There is no need to communicate bulky intermediate data among worker processes of the parallelized execution. This CIS(D) code is then incorporated into a developer version of ABINIT-MP program, in order to improve the overestimation in excitation energies calculated by the CIS method in conjunction with the multilayer fragment molecular orbital scheme (MLFMO-CIS) (Mochizuki et al. in Chem Phys Lett 406:283, 2005). The MLFMO-CIS(D) method is first used in evaluating the lowest n\(\pi^{*}\) excitation energy of the hydrated formaldehyde. The photoactive yellow protein (PYP) is the second target of MLFMO-CIS(D) calculation. Through these applications, it is shown that the CIS(D) correction improves the CIS results favorably.     

Ab initio molecular orbital calculations

A series of non-empirical calculations on furan, pyrrole and 1,2,5-oxadiazole are reported in which the effect of polarisation functions added to the minimal 7s 3p basis on each atom is studied. The effect on these planar molecules is largely through the rather than the-system. A comparison with the results of work with scaled functions is reported. Both series are shown to lead to much improved agreement with the electron spectroscopy energy levels. The effect on the dipole moments of these changes in basis is more variable but, with the exception of furan, the agreement with experiment is improved in the present method.

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Zusammenfassung Für die Moleküle Furan, Pyrrol und 1,2,5-Oxadiazol wurde eine Reihe von nichtempirischen Rechnungen durchgeführt, in denen der Einfluß von zusätzlichen Polarisationsfunktionen zur minimalen 7s 3p-Basis an jedem Atom untersucht wird. Die Ergebnisse werden mehr durch die Art der Beschreibung des Systems der-Elektronen als durch diejenige der-Elektronen beeinflußt. Ein Vergleich mit den Ergebnissen bei Verwendung skalierter Funktionen wird durchgeführt. Beide Reihen von Ergebnissen zeigen eine verbesserte Übereinstimmung zu den Energiemeßwerten der Elektronenspektroskopie. Die Änderungen des berechneten Dipolmoments bei derartigen Basisvariationen sind größer als bei früheren Methoden. Die Übereinstimmung mit dem Experiment wird, mit Ausnahme von Furan, jedoch verbessert.

     

Ab Initio molecular orbital calculations

Linear combinations of Gaussian orbitals were contracted to minimal basis sets. The binding energies (B.E.) obtained for the three compounds furan, pyrrole and 1,2,5-oxadiazole are 0.75, 0.84 and 0.26 a.u. respectively. Correlation of these figures and those obtained in related calculations leads to the relationship (B.E.)_exp.=0.7347 (B.E.)_calc.+633 (Kcal/mole). The photoelectron spectra of these compounds are extended and correlated with the orbital energies; the -electron excitations are given by (I.P.)_exp.=1.00 (I.P.)_calc.–2.20 eV. Mulliken population analyses give dipole moments in reasonable agreement with experiment.

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Zusammenfassung Linearkombinationen von Gauß-Orbitalen wurden zu minimalen Basissätzen kontrahiert.Die Bindungsenergien (B.E.) für die drei Komponenten Furan, Pyrrol und 1,2,5-Oxadiazol haben die Werte: 0,75, 0,84 und 0,26 a.u. Setzt man diese Werte zu den berechneten in Beziehung, so erhält man die Gleichung: (B.E.)_exp.=0,7347 (B.E.)_calc.+633 (Kcal/Mol).Die Photoelektronenspektren dieser drei Komponenten werden erweitert und mit den Orbitalenergien korreliert; die -Elektronen-Anregungsenergien werden durch die Beziehung: (I.P.)_exp. =1.00 (I.P.)_calc.–2,20 eV gegeben. Mulliken-Populations-Analysen ergeben die Dipolmomente in bemerkenswerter Übereinstimmung mit experimentellen Werten.

     

Assessment and acceleration of binding energy calculations for protein–ligand complexes by the fragment molecular orbital method

In the field of drug discovery, it is important to accurately predict the binding affinities between target proteins and drug applicant molecules. Many of the computational methods available for evaluating binding affinities have adopted molecular mechanics‐based force fields, although they cannot fully describe protein–ligand interactions. A noteworthy computational method in development involves large‐scale electronic structure calculations. Fragment molecular orbital (FMO) method, which is one of such large‐scale calculation techniques, is applied in this study for calculating the binding energies between proteins and ligands. By testing the effects of specific FMO calculation conditions (including fragmentation size, basis sets, electron correlation, exchange‐correlation functionals, and solvation effects) on the binding energies of the FK506‐binding protein and 10 ligand complex molecule, we have found that the standard FMO calculation condition, FMO2‐MP2/6‐31G(d), is suitable for evaluating the protein–ligand interactions. The correlation coefficient between the binding energies calculated with this FMO calculation condition and experimental values is determined to be R = 0.77. Based on these results, we also propose a practical scheme for predicting binding affinities by combining the FMO method with the quantitative structure–activity relationship (QSAR) model. The results of this combined method can be directly compared with experimental binding affinities. The FMO and QSAR combined scheme shows a higher correlation with experimental data (R = 0.91). Furthermore, we propose an acceleration scheme for the binding energy calculations using a multilayer FMO method focusing on the protein–ligand interaction distance. Our acceleration scheme, which uses FMO2‐HF/STO‐3G:MP2/6‐31G(d) at R_int = 7.0 Å, reduces computational costs, while maintaining accuracy in the evaluation of binding energy. © 2015 Wiley Periodicals, Inc.     

Semiempirical molecular orbital calculations on boranes

Traditional Pariser-Parr-Pople and variable electronegativity calculations have been carried out on C₆H₅B(OR)₂ and p-CH₃OC₆H₄B(OR)₂, and the results compared with calculations for C₆H₅BR₂. It is concluded that the VE-SCF method offers a real advantage over the simple PPP method for predicting percent charge transfer and transition intensity in cases where excited states possess substantial C.T. character. The restriction that empirically chosen parameters fit the observed transition energies and intensities of both triarylboranes and ArB(OR)₂ requires the choice of a boron VSIP greater than 2.0 eV in the fixed parameter procedure of the usual PPP-SCF-CI method for these molecules. Observed transitions in C₆H₅B(OR)₂ correlate with ¹ L _b, ¹ L _a, ¹ B _b, whereas the first absorption maximum of (C₆H₅)₃B is assigned to C.T. (¹ A ₁¹ A ₁) local C _2v symmetry.

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Zusammenfassung PPP- und VE SCF-Rechnungen wurden für C₆H₅B(OR)₂ und p-CH₃OC₆H₄(OR)₂ durch- geführt, und die Ergebnisse wurden mit denjenigen für C₆H₅BR₂ verglichen. Es kann der Schluß gezogen werden, daß die VE SCF-Methode einen Vorteil gegenüber der einfachen PPP-Methode bietet, um den prozentualen Charge Transfer und Übergangsintensitäten in Fällen zu bestimmen, in denen die angeregten Zustände einen wesentlichen C.T.-Charakter besitzen. Die Bedingung, daß die empirisch gewählten Parameter den beobachteten Übergangsenergien und -intensitäten von sowohl Triarylboranen als auch ArB(OR)₂ angepaßt sein sollen, erfordert die Wahl eines Bor-VSIP größer als 2,0 eV im Rahmen der üblichen Parametrisierung der PPP-SCF-CI-Methode. Beobachtete Über-gänge in C₆H₅B(OR)₂ korrelieren mit ¹ L _b, ¹ L _a, ¹ B _b, wogegen das erste Absorptionsmaximum des (C₆H₅)₃B einem C.T.-Übergang (¹ A ₁¹ A ₁) lokaler C_2v -Symmetrie zugeordnet wird.

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Résumé Des calculs traditionnels Pariser-Parr-Pople et des calculs d'électronégativité variable ont été effectués sur C₆H₅B(OR)₂ et p-CH₃OC₆H₄B(OR)₂ avec comparison aux résultats obtenus pour C₆H₅BR₂. La conclusion est que la méthode VE-SCF offre un réel avantage sur la méthode PPP simple en ce qui concerne la prédiction du transfert de charge et de l'intensité de transition pour les états excités possédant un net caractère de transfert de charge. La restriction selon laquelle les paramètres empiriques doivent permettre de reproduire les énergies de transition et les intensités des deux triarylboranes et de ArB(OR)₂, nécessite le choix d'un potential d'ionisation de l'état de valence du bore supérieur de 2 eV à celui employé dans les méthodes ordinaires. Les transitions observées dans C₆H₅B(OR)₂ sont reliées à ¹ L _b, ¹ L _a, ¹ B _b, tandis que la première absorption de (C₆H₅)₃B est attribuée à un transfert de charge (¹ A ₁¹ A ₁) de symétrie locale C_2v.

     

Flavin enzymes: molecular orbital calculations

Molecular orbital calculations were obtained for one hundred and forty-four versions of the flavin group contained in oxidase enzymes. Ten different structures were considered and the results indicate that the flavin group changes its identity from a pi electron acceptor to a pi electron donor after reduction occurs, regardless of the inductive effect of the attached protein. Furthermore, the calculations suggest both the site for reduction and the mechanism by which it proceeds.     

Semi-empirical molecular orbital calculations for pyridinealdoximes and acetamidopyridines

Tautomerism of pyridinealdoximes and acetamidopyridines is discussed with regard to their electronic absorption spectra. The spectra of both neutral and ionic forms of the molecules are interpreted by means of the Pariser—Parr—Pople type of calculation in a satisfactory way.The stability of 2- and 4-pyridinealdoxime tautomers is investigated using the CNDO/2 method. The lactim are more stable than the lactam forms of the molecules. The molecules having the substituent group of the syn-configuration are more stable than the molecules with other configurations of the substituent.     

Self-consistent molecular orbital calculations on organoboron compounds

The Pariser-Parr-Pople method has been used to calculate the electronic structures and spectra of three methylvinylboranes. Two separate calculational models of the methyl group are considered and the agreement between observed and calculated spectral quantities is good. The reorganisation energies of these molecules are also evaluated.

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Zusammenfassung Mit der Methode von Pariser, Pople und Parr werden Struktur und Spektren der -Elektronensysteme von drei Methylvinylboranen berechnet, ebenso ihre Reorganisationsenergien. Für die Methylgruppe werden zwei verschiedene Modelle verwendet. Die übereinstimmung zwischen berechneten und experimentellen Werten ist gut.

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Résumé A l'aide de la méthode Pariser-Parr-Pople nous avons calculé les structures et les spectres -électroniques de trois méthylvinylboranes. Nous considérons deux modèles du groupe méthyl; les spectres observés et calculés s'accordent bien. En plus, les énergies de réorganisation de ces molécules sont évaluées.

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One of us (D.R.A.) wishes to thank the S.R.C. for a maintenance grant.     

Self-consistent molecular orbital calculations on organoboron compounds

The electronic structures of three dihalogenophenylboranes have been investigated by the Pariser-Parr-Pople method. The agreement between the observed and calculated electronic spectra is quite good.

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Zusammenfassung Die -Elektronen-Strukturen von drei Dihalogenphenylboranen wurden mit der PPP-Methode untersucht. Beobachtete und berechnete Elektronenspektren stimmen recht gut überein.

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Résumé On a étudié par la méthode de Pariser-Parr-Pople les structures électroniques de trois dihalogénophenylboranes. L'accord entre les spectres électroniques observés et calculés est assez satisfaisant.

     

Self-consistent molecular orbital calculations on organoboron compounds

The PPP-SCMO-method is used to calculate the energies of the ground and lower excited states of triphenylborane and tri-p-tolylborane for which both planar and propellor models are considered. It is found necessary to include a large measure of configuration interaction in the excited states in order to produce satisfactory agreement with published u.v. spectra. However the calculations are not diagnostic for the detailed geometry of these compounds. The electronic spectra may be interpreted in terms of ring exciton states and interring and phenyl-boron charge-resonance states. The electron density on the central atom and the B-C bond orders are small and so the phenyl rings are but little perturbed by their bonding to boron.

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Zusammenfassung PPP-SCMO-Rechnungen wurden für Triphenyl- und Tri-p-tolylboran durchgeführt. Ohne ausgedehnte Konfigurationenwechselwirkung erhält man keine befriedigende Übereinstimmung mit veröffentlichten UV-Spektren. Die Deutung der Elektronenspektren geschieht mit Hilfe der Begriffe der einzelnen Einganregung sowie des Ring-Ring- und des Ring-Bor-Ladungsaustausches. Ob die Molekeln in einer planaren oder einer Propeller-Konformation vorliegen, kann aufgrund dieser Rechnungen nicht entschieden werden. Bor--Ladung und B-C--Bindungsordnung sind gering; die Phenylringe werden durch ihre Bindung an Bor kaum beeinflußt.

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Résumé La méthode SCMO-PPP a été utilisée pour calculer les énergies de l'état fondamental et des plus bas états excités du triphènylborane et du tri-p-tolylborane pour lequel on a considéré les modèles plan et en hêlice de bâteau. L'inclusion d'une interaction de configurations étendue entre états excités est nécessaire pour obtenir un accord satisfaisant avec les spectres UV publiés. Mais les calculs ne permettent pas de préciser la géométrie détaillée de ces composés. Les spectres électroniques peuvent être interprétés en termes d'états excitoniques du cycle et d'états de résonance de charge entre cycles et entre le phényl et le bore. La densité électronique sur l'atome central et les indices de liaison sur les liaisons B-C sont faibles ce qui montre que les noyaux phényliques sont peu perturbés par leur liaison au bore.

     

Multitargeting by curcumin as revealed by molecular interaction studies

Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic molecule with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex molecular structure and chemistry, as well as its ability to influence multiple signaling molecules. Curcumin has been shown to bind by multiple forces directly to numerous signaling molecules, such as inflammatory molecules, cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca(2+) ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto-enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromolecules include the α, β-unsaturated β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the phenyl rings. Various biophysical tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform infrared (FTIR) and circular dichroism (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunoprecipitation, phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Molecular docking, the most commonly employed computational tool for calculating binding affinities and predicting binding sites, has also been used to further characterize curcumin's binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its solubility and bioavailability. In this review, we focus on how curcumin directly targets signaling molecules, as well as the different forces that bind the curcumin-protein complex and how this interaction affects the biological properties of proteins. We will also discuss various analogues of curcumin designed to bind selective targets with increased affinity.     

Molecular orbital calculations based on linear combinations of fragment orbitals

A semiempirical MO method based on localized fragment orbitals has been developed, which is particularly suited for the construction of orbital correlation diagrams for the discussion of the electronic structure of complex molecules in terms of fragments and their interactions. The method allows for the inclusion of experimental ionization potentials and electron affinities of the fragments within the calculation of the Fock matrix elements and may thus form the basis of an interpretation of photoelectron spectra, comparable to the interpretation of UV spectra by means of the MIM method of Longuet-Higgins and Murrell. Several levels of approximation are discussed using the acrolein molecule as an example.