Anita M. Orendt

Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test

The results of the fifth blind test of crystal structure prediction, which show important success with more challenging large and flexible molecules, are presented and discussed.

Report on the sixth blind test of organic crystal structure prediction methods

The results of the sixth blind test of organic crystal structure prediction methods are presented and discussed, highlighting progress for salts, hydrates and bulky flexible molecules, as well as on-going challenges.

Quantum mechanically derived AMBER‐compatible heme parameters for various states of the cytochrome P450 catalytic cycle

Molecular mechanics (MM) methods are computationally affordable tools for screening chemical libraries of novel compounds for sites of P450 metabolism. One challenge for MM methods has been the absence of a consistent and transferable set of parameters for the heme within the P450 active site. Experimental data indicate that mammalian P450 enzymes vary greatly in the size, architecture, and plasticity of their active sites. Thus, obtaining X‐ray‐based geometries for the development of accurate MM parameters for the major classes of hepatic P450 remains a daunting task. Our previous work with preliminary gas‐phase quantum mechanics (QM)‐derived atomic partial charges greatly improved the accuracy of docking studies of raloxifene to CYP3A4. We have therefore developed and tested a consistent set of transferable MM parameters based on gas‐phase QM calculations of two model systems of the heme—a truncated (T‐HM) and a full (F‐HM) for four states of the P450 catalytic cycle. Our results indicate that the use of the atomic partial charges from the F‐HM further improves the accuracy of docked predictions for raloxifene to CYP3A4. Different patterns for substrate docking are also observed depending on the choice of heme model and state. Newly parameterized heme models are tested in implicit and explicitly solvated MD simulations in the absence and presence of enzyme structures, for CYP3A4, and appear to be stable on the nanosecond simulation timescale. The new force field for the various heme states may aid the community for simulations of P450 enzymes and other heme‐containing enzymes.

Solid-State Effects on NMR Chemical Shifts

This review presents first a qualitative description of the changes observed in the measured chemical shifts in solid state when compared with those obtained in solution. This qualitative description of the intermolecular interactions that affect the chemical shifts is followed by a comprehensive description of the theoretical methods available to analyze the solid-state effects on the chemical shifts. There are numerous examples of solid-state effects in the literature; here we have selected some of the most notable ones, which are presented as case studies. These case studies are classified by nuclei and by the dominant interaction that defines the solid-state effects. Examples are presented for 13 C, 15/14 N, 1 H, 17 O, 31 P, and 19 F. In addition to the effects discussed for chemical shifts the review also presents examples of the solid-state effects on the quadrupolar constants in the case of non 1/2 spin nuclei.

Measurement of 13C chemical shift tensor principal values with a magic-angle turning experiment

The magic-angle turning (MAT) experiment introduced by Gan is developed into a powerful and routine method for measuring the principal values of 13C chemical shift tensors in powdered solids. A large-volume MAT probe with stable rotation frequencies down to 22 Hz is described. A triple-echo MAT pulse sequence is introduced to improve the quality of the two-dimensional baseplane. It is shown that measurements of the principal values of chemical shift tensors in complex compounds can be enhanced by using either short contact times or dipolar dephasing pulse sequences to isolate the powder patterns from protonated or non-protonated carbons, respectively. A model compound, 1,2,3-trimethoxybenzene, is used to demonstrate these techniques, and the 13C principal values in 2,3-dimethylnaphthalene and Pocahontas coal are reported as typical examples.

Iglo calculations of the antisymmetric components of nuclear magnetic shielding tensors

Abstract Calculations of the antisymmetric components of 13 C shielding tensors have been performed in several compounds using the IGLO (individual gauge for localized orbitals) method. The results indicate chemical situations in which the detection of the antisymmetric components should be easier than in the cases analyzed by Iwai and Saika.

Low temperature 13C NMR magnetic resonance in solids 4. Cyclopropane, bicyclo[1.1.0]butane and [1.1.1] propellane

The solid state 13C NMR spectra of bicyclo[1.1.0]butane and [1.1.1]propellane have been measured at low temperature. The orientation of the principal axes of the chemical shielding tensor have been determined with ab initio calculations based on the IGLO (Individual Gauge for Localized Orbitals) method when they are not determined by symmetry. Excellent agreement is obtained between the calculated and experimental principal values of the shielding tensor when basis sets containing polarization functions are used. In most cases the agreement is such that the calculated values are within the experimental error.

Crystal structure prediction of flexible molecules using parallel genetic algorithms with a standard force field.

This article describes the application of our distributed computing framework for crystal structure prediction (CSP) the modified genetic algorithms for crystal and cluster prediction (MGAC), to predict the crystal structure of flexible molecules using the general Amber force field (GAFF) and the CHARMM program. The MGAC distributed computing framework includes a series of tightly integrated computer programs for generating the molecules force field, sampling crystal structures using a distributed parallel genetic algorithm and local energy minimization of the structures followed by the classifying, sorting, and archiving of the most relevant structures. Our results indicate that the method can consistently find the experimentally known crystal structures of flexible molecules, but the number of missing structures and poor ranking observed in some crystals show the need for further improvement of the potential.

Isolation of pyrrolocins A-C: cis- and trans-decalin tetramic acid antibiotics from an endophytic fungal-derived pathway.

Three new decalin-type tetramic acid analogues, pyrrolocins A (1), B (2), and C (3), were defined as products of a metabolic pathway from a fern endophyte, NRRL 50135, from Papua New Guinea. NRRL 50135 initially produced 1 but ceased its production before chemical or biological evaluation could be completed. Upon transfer of the biosynthetic pathway to a model host, 1–3 were produced. All three compounds are structurally related to equisetin-type compounds, with 1 and 3 having a trans-decalin ring system, while 2 has a cis-fused decalin. All were active against Mycobacterium tuberculosis, with the trans-decalin analogues 1 and 3 exhibiting lower MICs than the cis-decalin analogue 2. Here we report the isolation, structure elucidation, and antimycobacterial activities of 1–3 from the recombinant expression as well as the isolation of 1 from the wild-type fungus NRRL 50135.

Self-assembly of a triangle-shaped, hexaplatinum-incorporated, supramolecular amphiphile in solution and at interfaces.

The self-assembly and characterization of a novel supramolecular amphiphile built from a new 60 degree amphiphilic precursor that incorporates hydrophilic platinum(II) metals and hydrophobic dioctadecyloxy chains is reported. The amphiphilic macrocycle and its precursor compound have been characterized by multinuclear NMR spectroscopy, ESI-MS, and other standard techniques. The coacervate morphology of the amphiphile at the liquid-liquid interface has been studied by using confocal optical microscopy and in situ Raman spectroscopy. The self-assembly of the amphiphilic macrocycle at the air-water interface has been investigated through Langmuir-trough techniques. The study indicates the possible formation of surface micelle-like aggregates. The disparity between the experimental molecular areas and those derived from molecular models support the idea of aggregation. AFM images of the surface aggregates show the formation of a flat topology with arbitrary ridgelike patterns. Reasonable molecular-packing arrangements are proposed to explain the molecular organization within the observed structures.