Modeling of serine protease prototype reactions with the flexible effective fragment potential quantum mechanical/molecular mechanical method

A complete cycle of chemical transformations for the serine protease prototype reaction is modeled following calculations with the flexible effective fragment quantum mechanical/molecular mechanical (QM/MM) method. The initial molecular model is based on the crystal structure of the trypsin–bovine pancreatic trypsin inhibitor complex including all atoms of the enzyme within approximately 15–18 Å of the oxygen center O of the catalytic serine residue. Several selections of the QM/MM partitioning are considered. Fractions of the side chains of the residues from the catalytic triad (serine, histidine and aspartic acid) and a central part of a model substrate around the C–N bond to be cleaved are included into the QM subsystem. The remaining part, or the MM subsystem, is represented by flexible chains of small effective fragments, whose potentials explicitly contribute to the Hamiltonian of the QM part, but the corresponding fragment–fragment interactions are described by the MM force fields. The QM/MM boundaries are extended over the C–C bonds of the peptides assigned to the QM subsystem in the enzyme, C–C and C–N bonds in model substrates. Multiple geometry optimizations have been performed by using the RHF/6-31G method in the QM part and OPLSAA or AMBER sets of MM parameters, resulting in a series of stationary points on the complex potential-energy surfaces. All structures generally accepted for the serine protease catalytic cycle have been located. Energies at the stationary points found have been recomputed at the MP2/6-31+G^* level for the QM part in the protein environment. Structural changes along the reaction path are analyzed with special attention to hydrogen-bonding networks. In the case of a model substrate selected as a short peptide CH₃(NHCO-CH₂)₂ – HN–CO–(CH₂–NHCO)CH₃ the computed energy profile for the acylation step shows too high activation energy barriers. The energetics of this rate-limiting step is considerably improved, if more realistic model for the substrate is considered, following the motifs of the ThrI11–GlyI12–ProI13-–CysI14–LysI15–AlaI16–ArgI17–IleI18–IleI19 sequence of the bovine pancreatic trypsin inhibitor.     

Synthesis and Structure of Some N-[3-(Het)aryl-2-propenylidene]trifluoromethylanilines

The reactions of 4-nitrocinnamaldehyde with trifluoromethylanilines in the presence of molecular sieves were studied, and a series of new aromatic and heterocyclic aldimines were synthesized. The molecular and crystal structure of some of them were determined by X-ray crystallographic analysis.     

Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).     

Molecular caps for full quantum mechanical computation of peptide-water interaction energy

We present a systematic study of numerical accuracy of various forms of molecular caps that are employed in a recently developed molecular fractionation scheme for full quantum mechanical computation of protein-molecule interaction energy. A previously studied pentapeptide (Gly-Ser-Ala-Asp-Val) or P5 interacting with a water molecule is used as a benchmark system for numerical testing. One-dimensional potential energy curves are generated for a number of peptide-water interaction pathways. Our study shows that various forms of caps all give consistently accurate energies compared to the corresponding full system calculation with only small deviations. We also tested the accuracy of cutting peptide backbone at different positions and comparisons of results are presented.     

Electronically-coupled MM quadruply-bonded complexes of molybdenum and tungsten

The reaction of M2(O2CBu(t))4 (M = Mo, W) with a dicarboxylic acid in toluene yields compounds of general formula [M2]-O2C-X-CO2-[M2] ([M2] = M2(O2CBu(t))3; X = conjugated spacer). The M2 units are electronically coupled via interactions between the M2 delta and dicarboxylate pi* orbitals, and the magnitude of this coupling is revealed by electronic structure calculations and spectroscopic data. These compounds show intense metal to ligand charge transfer (MLCT) absorptions in the visible region of the electronic spectrum that are temperature and solvent dependent. Evidence of electronic coupling is seen in their cyclic voltammograms, which show two successive one-electron oxidations. The extent of electronic coupling in the mixed valence radical cations [M2]-O2C-X-CO2-[M2]+, generated by oxidation with one equivalent of AgPF6 or FeCp2PF6, is evaluated by EPR and UV-vis-NIR spectroscopic data, and delocalized behavior is observed in compounds with W2 units separated by up to 13.6 angstroms. The simplicity of the frontier M2 orbital interactions with the bridge pi orbitals provides a convenient system with which to study electron transfer in mixed valence systems, as compared to the extensively studied, but more complicated, dinuclear t(2g)6/t(2g)5 mixed valence compounds. Oligomeric and polymeric compounds incorporating M2 units have also been synthesized, having general formula [M2(O2CR)2(O2C-Thio-CO2)]n (Thio = n-hexyl substituted ter- and quinque-thiophenes). They can be deposited as thin films by spin coating, and show photoluminescence and electroluminescence. These metallo-polythiophenes show potential for application in electronic materials. (     

A computational model of the nicotinic acetylcholine binding site

We have derived a model of the nicotinic acetylcholine binding site. This was accomplished by using three known agonists (acetylcholine, nicotine and epibatidine) as templates around which polypeptide side chains, found to be part of the receptor cavity from published molecular biology studies, are allowed to flow freely in molecular dynamics simulations and mold themselves around these templates. The resulting supramolecular complex should thus be a complement, both in terms of steric effects as well as electronic effects, to the agonists and it should be a good estimation of the true receptor cavity structure. The shapes of those minireceptor cavities equilibrated rapidly on the simulation time scale and their structural congruence is very high, implying that a satisfactory model of the nicotinic acetylcholine binding site has been achieved. The computational methodology was internally tested against two rigid and specific antagonists (dihydro--erytroidine and erysoidine), that are expected to give rise to a somewhat differently shaped binding site compared to that derived from the agonists. Using these antagonists as templates there were structural reorganizations of the initial receptor cavities leading to distinctly different cavities compared to agonists. This indicates that adequate times and temperatures were used in our computational protocols to achieve equilibrium structures for the agonists. Overall, both minireceptor geometries for agonists and antagonists are similar with the exception of one amino acid (ARG209).     

Solubility enhancement of triflumizole by host-guest interaction with β-cyclodextrin

Summary The solubility enhancement of triflumizole, a systemic fungicide, by -cyclodextrin inclusion complexation was investigated by electron absorption spectroscopy. The respective association constant determined by different methods was estimated to 470±20M ^–1 in aqueous solution. A model for the host-guest complexation was deduced by molecular calculations.

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Löslichkeitsverbesserung von Triflumizole durchHost-Guest-Complexierung mit -Cyclodextrin

Zusammenfassung Die Löslichkeitsverbesserung des systemischen Fungizids Triflumizole durch Komplexierung mit -Cyclodextrin wurde mittels Elektronenabsorptionsspektroskopie untersucht. Die entsprechende Stabilitätskonstante wurde durch verschiedene Methoden erfaßt und betrug im wäßrigen Medium 470±20M ^–1. Ein Model für denHost-Guest-Complex wurde durch Molekülrechnungen erstellt.

     

Ab initio study of the ground state and conformational stability of peroxyacetyl nitrate in internal rotation about the peroxide bond

The molecular and electronic structure of the ground state of peroxyacetyl nitrate (PAN) was calculated by the unrestricted Hartree-Fock-Roothaan method with the use of the standard 3–21G and 6–31G basis set. The potential curve of the internal rotation about the peroxide bond of PAN was calculated with the 6–31G basis set. The curve contains two maxima. The ground state of PAN is characterized by a structure in which groups of atoms adjacent to the peroxide bond lie in planes that are perpendicular to each other (the dihedral angle ϱ(COON) is 89.9°). The calculated barriers to rotation are 19.6 and 66.8 kJ mol⁻¹. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 600–604, April, 1998.     

A force field study of diacetylene molecule by kinetic constant method

The potential constants of diacetylene molecule has been evaluated using kinetic constants. The other molecular constants such as the generalised vibrational mean amplitudes, shrinkage constants, Coriolis coupling constants and centrifugal distortion constants are also calculated using the vibrational frequencies and the results discussed.     

Linear scaling local correlation approach for solving the coupled cluster equations of large systems

A linear scaling local correlation approach is proposed for approximately solving the coupled cluster doubles (CCD) equations of large systems in a basis of orthogonal localized molecular orbitals (LMOs). By restricting double excitations from spatially close occupied LMOs into their associated virtual LMOs, the number of significant excitation amplitudes scales only linearly with molecular size in large molecules. Significant amplitudes are obtained to a very good approximation by solving the CCD equations of various subsystems, each of which is made up of a cluster associated with the orbital indices of a subset of significant amplitudes and the local environmental domain of the cluster. The combined effect of these two approximations leads to a linear scaling algorithm for large systems. By using typical thresholds, which are designed to target an energy accuracy, our numerical calculations for a wide range of molecules using the 6-31G or 6-31G* basis set demonstrate that the present local correlation approach recovers more than 98.5% of the conventional CCD correlation energy.