Non-covalent intermolecular interactions polarize a drug molecule in the biological environment to prepare it for the recognition and binding process with a related enzyme. In a crystal structure of the same drug molecule, the crystal packing is defined by the same kind of non-covalent interactions. This means that in both a biological as well as a crystalline environment, the small molecule will conformationally adapt its shape to the prevailing intermolecular binding forces, so that the resulting bound state reflects both its inherent flexibility and the environment. Electrostatic complementarity between an enzyme binding site and an active molecule is an aspect that goes beyond geometry and molecular conformation since the electrostatic potential is inherently related to the electron density distribution. We ask to which extent small-molecule crystal structures can be used to predict the conformation and interaction density of the same molecule in the enzyme.

The first compound class investigated is related to loxistatin acid E64c. These compounds are cysteine protease inhibitors, and the active site is an electrophilic epoxide ring.[1] It took us many years to solve the small-molecule crystal structure of E64c,[2] and experimental electron-density studies were only possible for related model compounds.[3] Recently, however, we were able to perform a full quantum-crystallographic, molecular-dynamics and QM/MM study of the active site of E64c co-crystallizing in a system that closely resembles the binding situation of E64c in the cysteine protease cathepsin B.[4]

The second compound class investigated refers to ibuprofen derivatives. We used the umpolung principle to tune the properties of ibuprofen by carbon-silicon exchange, which in turn impacts on the electrostatic complementarity relationships when ibuprofen binds to cyclooxygenases.[5] Again, we investigated the enzyme and crystal environmental effects on ibuprofen and sila-ibuprofen by quantum crystallography, molecular dynamics and QM/MM calculations.[6]

Every low-temperature high-resolution single-crystal X-ray diffraction experiment utilized in this study was conducted at a synchrotron beamline at either DESY, APS or SPring-8. Without access to large infrastructure, such studies on weakly scattering pharmaceutically active compounds would not be possible. I will therefore not only report the biochemically relevant results, but also the importance of synchrotron experiments for our field.

[1] Mladenovic, M., Ansorg, K., Fink, R. F., Thiel, W., Schirmeister, T. & Engels, B. (2008). J. Phys. Chem. B, 112, 11798.
[2] Shi, M. W., Sobolev, A. N., Schirmeister, T., Engels, B., Schmidt, T. C., Luger, P., Mebs, S., Dittrich, B., Chen, Y.-S., Bąk, J. M., Jayatilaka, D., Bond, C. S., Turner, M. J., Stewart, S. G., Spackman, M. A. & Grabowsky, S. (2015). New J. Chem. 39, 1628.
[3] Grabowsky, S., Schirmeister, T., Paulmann, C., Pfeuffer, T. & Luger, P. (2011). J. Org. Chem. 76, 1305.
[4] Kleemiss, F., Wieduwilt, E. K., Hupf, E., Shi, M. W., Stewart, S. G., Jayatilaka, D., Turner, M. J., Sugimoto, K., Nishibori, E., Schirmeister, T., Schmidt, T. C., Engels, B. & Grabowsky, S. (2021). Chem. Eur. J. 27, 3407.
[5] Kleemiss, F., Justies, A., Duvinage, D., Watermann, P., Ehrke, E., Sugimoto, K., Fugel, M., Malaspina, L. A., Dittmer, A., Kleemiss, T., Puylaert, P., King, N. R., Staubitz, A., Tzschentke, T. M., Dringen, R., Grabowsky, S. & Beckmann, J. (2020). J. Med. Chem. 63, 12614.
[6] Kleemiss, F., Duvinage, D., Puylaert, P., Fugel, M., Sugimoto, K., Beckmann, J. & Grabowsky, S. (2021). Acta Cryst. B, in preparation.

Visualizing on the atomic scale the full extent of the electronic and structural changes that are triggered by charge separation and subsequent charge transport is crucial for developing the rational design of novel sensitizers and catalysts. The rapid progress of ultrafast X-ray techniques, both at synchrotrons (100 ps) and at X-ray free electron laser facilities (sub-ps) have equipped the scientific community with novel analytical tools that are capable of delivering unique feedback with spin and elemental sensitivity about the highly-correlated nonadiabatic dynamics that follow photoabsorption. The present talk will review the technical state-of-the art and the ongoing developments that are currently taking place. The talk will also highlight several of the recent results that have been obtained for intramolecular and interfacial processes of relevance for the function and optimization of advanced materials.

Photoactive materials are among the most commonly researched and engineered functional materials, due to the multiplicity of applications they find in research and industry. Investigating of the dynamics of short-lived excited states in crystal structures allows us to extract information on how such materials could be designed on the molecular level in order to obtain desired properties. Coordination compounds containing group XI transition-metal atoms, such as copper (I), silver(I), or gold(I), are excellent examples of compounds with interesting and diverse photoactive properties, and thus were chosen for this study.

Time-resolved photocrystallographic methods allow us to investigate structural changes occurring due to formation of short-lived laser-induced excited-state species in crystals. For the following study, several coinage-metal mononuclear and multinuclear coordination compounds were examined using time-resolved X-ray-pump / laser-probe Laue experiments, conducted at the 14-ID-B BioCARS APS synchrotron beamline. The studied complexes include the literature-reported Ag(PP)(PS) (PP = 1,2-bis(diphenylphosphino)ethane, PS = 2-(diphenylphospaneyl)pyridine) and newly-synthesised Ag₂Cu₂(PS)₄ systems, both exhibiting bright luminescence in the solid state. The time-resolved data were processed with our home-made software and the photodifference maps were generated and analysed.

In order to comprehensively understand excitation-induced effects occurring in crystals, the abovementioned photocrystallographic measurements were supplemented with time-resolved luminescence spectroscopy experiments (355 nm excitation wavelength) and quantum computations yielding the nature of studied exited states and predicting the geometry changes (TDDFT and QM/MM methods) upon excitation. Results will be presented, and their accordance with photocrystallographic results assessed.

The authors thank NSC (2016/21/D/ST4/03753, 2014/15/D/ST4/02856) and WCSS (grant No. 285) in Poland, EU programme (POIG.02.01.00-14-122/09) and APS, USA (DOE: DE-AC02-06CH11357, NIH: R24GM111072) for financial support and access to facilities.

High-resolution X-ray diffraction experiments, theoretical calculations and atom-specific X-ray absorption experiments are applied to investigate two nickel complexes [Ni(II) (A) and Ni(III) (B)] (Figure 1a, 1b) with the non-innocent 3,6-dichlorobenzene-1,2-dithiolate ligand. Combining the techniques of metal K-, L-edge and sulphur K-edge X-ray absorption spectroscopy with high-resolution X-ray charge density studies, the experimental assessment of oxidation states of the central Ni atoms is studied and compared with theoretical predictions. Furthermore, the experimentally derived X-ray charge density (obtained via the multipole model) and the electron density from theoretical calculations are provided to further explore the contrast and contest of both approaches employed.

Figure 1. Compounds(a) (A), (b) (B), (c) Laplacian of electron density

The oxidation state of the central atom will be discussed [1] (Figure 1c).

[1] Machata, P., Herich, P., Lušpai K., Bučinský, L., Šoralová, S., Breza, M., Kožíšek, J. & Rapta, P. (2014). Rev. Sci. Instrum. 70, 3554.

Organometallics 33 (18), 4846.

Carbonyl…carbonyl interactions have been identified in biologically active systems such as small biomolecules, proteins or protein-ligand complexes. Their contribution into molecular assembly was proven to be comparable to moderate hydrogen bonds, thus they can be considered as organic synthons playing crucial role in determining three-dimensional crystal packing or even stabilizing the secondary structure motifs of proteins. In the literature one can find many examples of C=O…C=O interactions between the same molecules, however to the best of our knowledge, only one case where such a pattern was characterized between different molecules (urea and oxalic acid co-crystal) [1].

Here we report a series of co-crystals of urea and dicarboxylic acid, where antiparallel carbonyl…carbonyl motif [2] between heteromolecules is observed and acts as a “glue” between 2D layers built of strong hydrogen bonds. In order to get inside into the nature and mechanism of the synthons, experimental and theoretical electron density studies were engaged as well as ETS-NOCV method (Extended Transition State. Natural Orbitals for Chemical Valence) was applied [3]. NCI analysis [4] and interaction energies calculated with EP/MM (Exact Potential and Multipole Method) method [5] indicate a correlation between the strength of carbonyl interactions and the number of carbon atoms in the main chain of the acid molecules.

Literature:

[1] A. Krawczuk, M. Gryl, M. Pitak, K. Stadnicka Cryst. Growth Des. (2015), 15, 5578−5592.

[2] F.H. Allen, I.J. Bruno Acta Crystallogr., Sect. B: Struct. Sci. (2010), 66, 380−386.

[3] F. Sagan, M. P. Mitoraj J. Phys. Chem. A (2019), 123, 21, 4616–4622

[4] E.R Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-Garciá, A.J. Cohen, W. Yang, J. Am. Chem. Soc. (2010), 132, 6498−6506.

[5] A. Volkov, T. Koritsanszky, P. Coppens, Chemical Physics Letters (2004), 391 (1–3), 170–175.

Hirshfeld atom refinement (HAR)[1,2] is one of the most successful methods for the accurate determination of structural parameters for hydrogen atoms from X-ray diffraction data. It employs atomic scattering factors based on atomic densities obtained via Hirshfeld partition of theoretically determined electron density.

There are various ways of calculating the electron density with theoretical methods. For example, among others, we can independently change (1) a method of quantum chemistry (2) basis set and (3) a representation of molecular environment. This a leads to obvious question – which set of settings is the best for HAR refinement?

An another dimension was recently added to the space of settings by introducing generalization of HAR to other electron density partitions [3] (so called generalized atom refinement (GAR)). This makes the optimal choice of settings even more challenging.

Another factor further complicates the situation – computational cost of GAR. Usually unfavorable scaling of quantum chemical calculations with size of a system may lead to long refinement time for large molecules. While computational chemistry brings here some solutions, we still have to figure out how to handle trade-off between computational cost and accuracy of refinement.

In this contribution we will analyze effects of various settings of GAR on accuracy of the method (assessed by comparison to neutron data). We will also try to find optimal solution for performing accurate refinement with optimized computational cost.

[1] Jayatilaka, D. & Dittrich, B. (2008). Acta Cryst. A64, 383–393.

[2] Capelli, S. C., Bürgi, H.-B., Dittrich, B., Grabowsky, S. & Jayatilaka, D. (2014). IUCrJ, 1, 361–379

[3] Chodkiewicz, M. L., Woińska, M. & Woźniak, K. (2020). IUCrJ, 7, 1199–1215.