A molecular modelling study of the interaction of noradrenaline with theβ 2-adrenergic receptor

Summary A model of the ₂-adrenergic receptor binding site is built from the primary structure of the receptor, experimental evidence for key binding residues and analogy with a homologous protein of partially determined structure. It is suggested that residues Trp-109, Thr-110 and Asp-113 are involved in ligand binding. Noradrenaline is successfully docked into this model, and the results of an INDO molecular orbital calculation on the complex indicate that a charge transfer interaction between Trp-109 and noradrenaline is possible.     

Computational study on the ring distortions of 1,4-dicyanobenzene in the gas phase and in the crystal

A molecular mechanics software enhanced to perform empirical energy calculations on crystals (KESSHOU) was further developed to handle intermolecular electrostatic interactions as well. The packing of the molecules of 1,4-dicyanobenzene and 1,4-diisocyanobenzene in the crystal was studied. The role of the van der Waals and the electrostatic interactions in the balance of nonbonded atom-atom interactions is analyzed. The packing forces are dominated by van der Waals forces. The electrostatic interactions have higher stabilizing contribution for the dicyano isomer than for the diisocyano form. The dependence of the results on the size of the crystal, the molecular mechanics force field (MM2 vs MM3), and the dielectric constant are also assessed. Ab initio MP2/6–311G** geometries of the isolated molecules are in accordance with the observed benzene ring distortions determined by electron diffraction.     

Complete-active-space self-consistent-field/Amber parameterization of the Lys296–retinal–Glu113 rhodopsin chromophore-counterion system

A special hybrid quantum mechanics/molecular mechanics forcefield is defined, parameterized and validated for studying the photoisomerization path of the retinal chromophore in the rhodopsin protein. It couples a multireference ab initio Hamiltonian (CASSCF and second-order multireference many-body perturbation theory using a CASSCF reference) to describe the chromophore while the rest of the protein is approximated with the Amber forcefield. The frontier has been carefully parameterized in order to reproduce full quantum mechanics torsional energy profiles, for both the ground state and the first excited state. It is also shown that replacing the chromophore counterion with point charges is a valid approximation. This result is interpreted in terms of a cancellation effect for which a possible explanation is given.     

Molecular modeling of intercalation complexes of antitumor active 9-aminoacridine and a [d,e]-anellated isoquinoline derivative with base paired deoxytetranucleotides

Summary Intercalators are molecules capable of sliding between DNA base pairs without breaking up the hydrogen bonds between the DNA bases. On the basis of molecular mechanics calculations structural, models of B-DNA tetranucleotide intercalation complexes of some cytostatic active 9-aminoacridines and of a [d, e]-anellated isoquinoline derivative are presented. The drug complexes are stabilized by energetically favouredvan der Waals interactions and by selective hydrogen bonds between the side chains of the drugs and the DNA bases. Semiempirical quantum chemistry calculations revealed that the chromophoric system of the intercalators is able to form ,-charge-transfer interactions with the purine bases of the base paired deoxytetranucleotides. The theoretical findings are of interest for a more specific drug design of cytostatically active agents.

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Molecular Modeling von Interkalationskomplexen antitumoraktiver 9-Aminoacridine sowie eines [d, e]-anellierten Isochinolinderivates mit basengepaarten Desoxytetranukleotiden

Zusammenfassung Interkalatoren sind Moleküle, die in der Lage sind, sich zwischen DNA-Basenpaare einzulagern, ohne die Wasserstoffbrücken zwischen den DNA-Basen aufzubrechen. Auf der Basis von molekülmechanischen Rechnungen werden Tetranukleotid-Interkalationskomplexe von verschiedenen zytostatisch aktiven 9-Aminoacridinen und von einem [d, e]-anellierten Isochinolinderivat präsentiert. Die Komplexe werden durch energetisch günstigevan der Waals-Interaktionen sowie durch selektive Wasserstoffbrückenbindungen zwischen den Seitenketten der Wirkstoffe und den DNA-Basen stabilisiert. Semiempirische quantenchemische Rechnungen ergaben, daß der Chromophor der Interkalatoren in der Lage ist, ,-charge-transfer Wechselwirkungen mit den Purinbasen der basengepaarten Desoxytetranukleotide auszubilden. Die theoretischen Ergebnisse sind für ein spezifischeres Wirkstoffdesign zytostatisch aktiver Verbindungen von Interesse.

     

Reverse-docking as a computational tool for the study of asymmetric organocatalysis

A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment. Clear energetic trends emerged from docking the catalyst to both enantiomers of all six azidation TS models of this study. Structural analysis of the most favorable pose suggests a mechanism for enantioselective catalysis that is consistent with principles of molecular recognition, catalysis, and experimental data.     

A structural analysis of the complexes of (S,S)-dimethylpyridino-18-crown-6 with (R) and (S)-[α-(1-naphthyl)ethyl]ammonium perchlorate by NMR techniques and molecular modeling

Significant - interaction is found in the complexes of (S, S)-dimethylpyridino-18-crown-6 with (R)- and (S)-[-(1-naphthyl)ethyl]ammonium perchlorate. This finding is supported by the¹H NOESY NMR spectral technique, greater chemical shift changes of aromatic protons in both host and guest molecules upon complexation, and by molecular mechanics calculations. Because of the flexibility of the ligand, the tripod hydrogen bonding causes¹³C relaxation times of all periphery carbons to decrease without significant selectivity. Rotational energy barrier calculations of the methyl groups of the complexed ligand also show that the (S, S)-host-(R)-guest is the more stable complex.     

Objective comparison of concentration profiles in solids by means of mathematical statistics

To compare concentration profiles in solids in an objective manner, a multi-dimensional generalization of the comparison of two means by Student'st-test is proposed. The approach is based on piecewise modelling the profiles using rougha priori information, estimating the model parameters and their covariance matrix and comparing the estimated parameters by use of multidimensional test variables. The piecewise modelling is treated in the most important cases in such a way that the partial functions are straight lines or cubic polynoms (splines) with continuity at all knots in each case. It enables us to compare whole profiles as well as the most relevant parts of them. Two ways of estimating the covariance matrix as a generalization of the variance estimation are discussed. The approach is useful for any kind of line profiles if rough information on the profile type is available. As an example SIMS depth-profiles of aluminum obtained from thin-layer systems after different technological heat treatments are considered. These profiles are modeled by three straight lines.     

Computer simulation of conformational movement based on interconversion phenomena

A computer method has been developed which is an alternative to molecular dynamics in the sense that it pictures conformational motion. It simulates propagation in conformational movement based on conformational interconversion phenomena. The method starts with the knowledge of the topology of the conformational potential energy hyper-surface, which is described by the minima and the transition states. The topology is obtained by the recently described software . The simulation of conformational motion is based on the Boltzmann statistics of movement between the minima and the transition states at a given temperature. The method is illustrated for methyl--glucopyranoside and - -galNAc(1-3)[- -Fuc(1-2)]Gal-O-Me molecules. Conformational transitions of hydroxyl groups as well as glycosidic linkages are discussed.     

Performance of SuSi: a method for generating atomistic models of amorphous polymers based on a random search of energy minima

The performance of a recently developed method to generate representative atomistic models of amorphous polymers has been investigated. This method, which is denoted SuSi, can be defined as a random generator of energy minima. The effects produced by different parameters used to define the size of the system and the characteristics of the generation algorithm have been examined. Calculations have been performed on poly(L,D-lactic) acid (rho = 1.25 g/cm3) and nylon 6 (rho = 1.084 g/cm(3)), which are important commercial polymers.