Crystal structure prediction of flexible pharmaceutical-like molecules: Density functional tight-binding as an intermediate optimization method and for free energy estimation

Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stage of CSP studies uses a relatively simple lattice energy approximation as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice-energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all inter and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15 ) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-function, to accurately describe the electrostatic component of the intermolecular energy. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking

A NOVEL FUSION 5'AFF3/3'BCL2 ORIGINATED FROM A t(2;18)(Q11.2-Q21.33) TRANSLOCATION IN FOLLICULAR LYMPHOMA

Follicular lymphoma is the second most frequent type of non-Hodgkin's lymphoma in adults. The basic molecular defect consists of the t(14;18)(q32;q21) translocation, juxtaposing the B-cell lymphoma protein 2 gene BCL2 to the immunoglobulin heavy chain locus IGH@, and leading to the antiapoptotic BCL2 protein overproduction. Variations in the t(14;18) are rare and can be classified into two categories: (i) simple variants, involving chromosomes 18 and 2, or 22, in which the fusion partner of BCL2 is the light-chain IGK@ or IGL@; (ii) complex variant translocations occurring among chromosomes 14, 18 and other chromosomes. We report a follicular lymphoma case showing BCL2 overexpression, detected by immunohistochemistry and real-time quantitative PCR, consequently to the formation of a novel fusion gene between the 5' of the lymphoid nuclear transcriptional activator gene AFF3 at 2q11.2, and the 3' of BCL2. This case shows evidence, for the first time, of BCL2 overexpression consequently to the fusion of BCL2 to a non-IG partner locus

Serendipitous isolation of a disappearing conformational polymorph of succinic acid challenges computational polymorph prediction

A conformational polymorph (γ) of succinic acid was discovered in an attempt to purify a leucine dipeptide by cocrystallization from a methanol solution in the presence of various impurities, such as trifluoroacetic acid. The new γ form was found to have crystallized concomitantly with the most stable β form. In light of this situation, a crystal structure prediction study was undertaken to examine the polymorph landscape. These studies reveal that the γ polymorph is thermodynamically competitive with the other observed polymorphs; having a more stable folded conformation than the planar crystalline conformation in the β form, but being stabilized less by the intermolecular interactions. Simulations and experiment show that the folded conformation is dominant in solution, but that trapping long-lived crystals of the new metastable polymorph may be challenging. Thus the γ polymorph provides a stringent test of theories for predicting which thermodynamically plausible structures may be practically important polymorphs

Towards the cryogenic sliding mechanism for MOONS-ESO

The Multi-Object Optical and Near-Infrared Spectrograph (MOONS) shall be installed at one of the Very Large Telescopes (VLT) at the European Southern Observatory (ESO) in Paranal Chile. The instrument is being designed and built by an international consortium on behalf of ESO. The design is based on a three arms configuration, RI, YJ and H band, where RI and H have two possible resolutions. To achieve this goal it will be necessary to implement a sliding mechanism changing the dispersers, the filters and the cross dispersion prisms. This article describes the cryogenic exchanger mechanism that is under realization and the preliminary mechanical and optical tests that we have done at the cryogenic facility of Arcetri observatory of Florence. Parts of these test are based on interferometric measurements of the optics to study the behaviour of the mechanical supporting structure, and part are based on the cryogenic sliding system that will be used to move approximately 200 Kg of mass for 350 mm of travel range. The cryogenic sliding system, rails, screws, motors, is based on commercial components as the position measurement device that is based on commercial potentiometers. The results of the tests and performances at cryogenic temperature are reported in this paper

Updated optical design and trade-off study for MOONS, the Multi-Object Optical and Near Infrared spectrometer for the VLT

This paper presents the latest optical design for the MOONS triple-arm spectrographs. MOONS will be a Multi-Object Optical and Near-infrared Spectrograph and will be installed on one of the European Southern Observatory (ESO) Very Large Telescopes (VLT). Included in this paper is a trade-off analysis of different types of collimators, cameras, dichroics and filters.Comment: 10 pages, 8 figures, 5 tables. Presented at SPIE Astronomical Telescope + Instrumentation 2014 (Ground-based and Airbone Instrumentation for Astronomy 5, 9147-84). To be published in Proceeding of SPIE Volume 914