Fast fragment- and compound-screening pipeline at the Swiss Light Source.

Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique. In recent years, technological advances at macromolecular crystallography beamlines in terms of instrumentation, beam intensity and robotics have enabled the development of dedicated platforms at synchrotron sources for FBDD using X-ray crystallography. Here, the development of the Fast Fragment and Compound Screening (FFCS) platform, an integrated next-generation pipeline for crystal soaking, handling and data collection which allows crystallography-based screening of protein crystals against hundreds of fragments and compounds, at the Swiss Light Source is reported.

The TELL automatic sample changer for macromolecular crystallography.

In this paper, the design and functionalities of the high-throughput TELL sample exchange system for macromolecular crystallography is presented. TELL was developed at the Paul Scherrer Institute with a focus on speed, storage capacity and reliability to serve the three macromolecular crystallography beamlines of the Swiss Light Source, as well as the SwissMX instrument at SwissFEL.

Automated data collection and real-time data analysis suite for serial synchrotron crystallography.

At the Swiss Light Source macromolecular crystallography (MX) beamlines the collection of serial synchrotron crystallography (SSX) diffraction data is facilitated by the recent DA+ data acquisition and analysis software developments. The SSX suite allows easy, efficient and high-throughput measurements on a large number of crystals. The fast continuous diffraction-based two-dimensional grid scan method allows initial location of microcrystals. The CY+ GUI utility enables efficient assessment of a grid scan's analysis output and subsequent collection of multiple wedges of data (so-called minisets) from automatically selected positions in a serial and automated way. The automated data processing (adp) routines adapted to the SSX data collection mode provide near real time analysis for data in both CBF and HDF5 formats. The automatic data merging (adm) is the latest extension of the DA+ data analysis software routines. It utilizes the sxdm (SSX data merging) package, which provides automatic online scaling and merging of minisets and allows identification of a minisets subset resulting in the best quality of the final merged data. The results of both adp and adm are sent to the MX MongoDB database and displayed in the web-based tracker, which provides the user with on-the-fly feedback about the experiment.

DA+ data acquisition and analysis software at the Swiss Light Source macromolecular crystallography beamlines.

Data acquisition software is an essential component of modern macromolecular crystallography (MX) beamlines, enabling efficient use of beam time at synchrotron facilities. Developed at the Paul Scherrer Institute, the DA+ data acquisition software is implemented at all three Swiss Light Source (SLS) MX beamlines. DA+ consists of distributed services and components written in Python and Java, which communicate via messaging and streaming technologies. The major components of DA+ are the user interface, acquisition engine, online processing and database. Immediate data quality feedback is achieved with distributed automatic data analysis routines. The software architecture enables exploration of the full potential of the latest instrumentation at the SLS MX beamlines, such as the SmarGon goniometer and the EIGER X 16M detector, and development of new data collection methods.

Multi-scale modelling of solvatochromic shifts from frozen-density embedding theory with non-uniform continuum model of the solvent: the coumarin 153 case.

For nine solvents of various polarity (from cyclohexane to water), the solvatochromic shifts of the lowest absorption band of coumarin 153 are evaluated using a computational method based on frozen-density embedding theory [Wesolowski and Warshel, J. Chem Phys., 1993, 97, 9050, and subsequent articles]. In the calculations, the average electron density of the solvent [linear span]ρ(B)(r[combining right harpoon above])[linear span] is used as the frozen density. [linear span]ρ(B)(r[combining right harpoon above])[linear span] is evaluated using the statistical-mechanical approach introduced in Kaminski et al., J. Phys. Chem. A, 2010, 114, 6082. The small deviations between experimental and calculated solvatochromic shifts (the average deviation equals to about 0.02 eV), confirm the adequacy of the key approximations applied: (a) in the evaluation of the average effect of the solvent on the excitation energy, using the average density of the solvent instead of averaging the shifts over statistical ensemble and (b) using the approximant for the bi-functional of the non-electrostatic component of the orbital-free embedding potential, are adequate for chromophores which interact with the environment by non-covalent bonds. The qualitative analyses of the origin of the solvatochromic shifts are made using the graphical representation of the orbital-free embedding potential.

Modeling solvatochromic shifts using the orbital-free embedding potential at statistically mechanically averaged solvent density.

The correspondence between the exact embedding potential and the pair of the electron densities--that of the embedded molecule and that of its environment [Wesolowski and Warshel, J. Phys. Chem. 1993, 97, 8050]--is used to generate the average embedding potential and to subsequently calculate the solvatochromic shifts in a number of organic chromophores in solvents of various polarities. The averaged embedding potential is evaluated at a fictitious electron density of the solvent, which is obtained by means of "dressing up" with electrons the classical site distributions derived from the statistical-mechanical, 3D molecular theory of solvation (aka 3D-RISM method) [Kovalenko In Molecular Theory of Solvation; Hirata, Ed.; Understanding Chemical Reactivity; 2003, Vol 24], self-consistently coupled with the electronic structure of the solute. The proposed approach to modeling solvatochromic shifts can be situated between the implicit and explicit type of models for the solvent. Numerical examples are given for the lowest-lying n --> pi* and pi --> pi* excitations.

Cooperative effect of hydrogen-bonded chains in the environment of a pi --> pi* chromophore.

Laser resonant two-photon ionization UV spectra provide clear evidence that the effect of increasing the length of the hydrogen-bonded chain consisting of molecules such as NH(3), H(2)O, or CH(3)OH on the pi --> pi* excitations of cis-7-hydroxyquinoline (cis-7HQ) is strongly cooperative [ Thut ; et al. J. Phys. Chem. A 2008 , 112 , 5566. ] A theoretical analysis of the experimental data is provided to identify the origin of this cooperativity for four chains. The computational method to determine the changes of the electronic structure of a molecule due to interactions with its environment uses the nonempirical expression for the embedding potential [ Wesolowski ; Warshel J. Phys. Chem. 1993 , 97 , 8050. ] It is concluded that the electronic coupling between the molecules at the ends of the chain, which are hydrogen-bonded to cis-7HQ, plays a crucial role in this cooperativity.

Orbital-free effective embedding potential at nuclear cusps.

A strategy to construct approximants to the kinetic-energy-functional dependent component (v(t)[rho(A),rho(B)](r)) of the effective potential in one-electron equations for orbitals embedded in a frozen-density environment [Eqs. (20) and (21) in Wesolowski and Warshel, J. Phys. Chem. 97, (1993) 8050] is proposed. In order to improve the local behavior of the orbital-free effective embedding potential near nuclei in the environment, the exact behavior of v(t)[rho(A),rho(B)](r) at rho(A)-->0 and integralrho(B)dr=2 is taken into account. As a result, the properties depending on the quality of this potential are invariably improved compared to the ones obtained using conventional approximants which violated the considered exact condition. The approximants obtained following the proposed strategy and especially the simplest one constructed in this work are nondecomposable, i.e., cannot be used to obtain the analytic expression for the functional of the total kinetic energy.

LiSc(BH4)4: a novel salt of Li+ and discrete Sc(BH4)4(-) complex anions.

LiSc(BH4)4 has been prepared by ball milling of LiBH4 and ScCl3. Vibrational spectroscopy indicates the presence of discrete Sc(BH4)4(-) ions. DFT calculations of this isolated complex ion confirm that it is a stable complex, and the calculated vibrational spectra agree well with the experimental ones. The four BH4(-) groups are oriented with a tilted plane of three hydrogen atoms directed to the central Sc ion, resulting in a global 8 + 4 coordination. The crystal structure obtained by high-resolution synchrotron powder diffraction reveals a tetragonal unit cell with a = 6.076 A and c = 12.034 A (space group P-42c). The local structure of the Sc(BH4)4(-) complex is refined as a distorted form of the theoretical structure. The Li ions are found to be disordered along the z axis.

Equilibrium Geometries of Noncovalently Bound Intermolecular Complexes Derived from Subsystem Formulation of Density Functional Theory.

The subsystem formulation of density functional theory is used to obtain equilibrium geometries and interaction energies for a representative set of noncovalently bound intermolecular complexes. The results are compared with literature benchmark data. The range of applicability of two considered approximations to the exchange-correlation- and nonadditive kinetic energy components of the total energy is determined. Local density approximation, which does not involve any empirical parameters, leads to excellent intermolecular equilibrium distances for hydrogen-bonded complexes (maximal error 0.13 Å for NH3-NH3). It is a method of choice for a wide class of weak intermolecular complexes including also dipole-bound and the ones formed by rare gas atoms or saturated hydrocarbons. The range of applicability of the chosen generalized gradient approximation, which was shown in our previous works to lead to good interaction energies in such complexes, where π-electrons are involved in the interaction, remains limited to this group because it improves neither binding energies nor equilibrium geometries in the wide class of complexes for which local density approximation is adequate. An efficient energy minimization procedure, in which optimization of the geometry and the electron density of each subsystem is made simultaneously, is proposed and tested.