CREST-A program for the exploration of low-energy molecular chemical space.

Conformer-rotamer sampling tool (CREST) is an open-source program for the efficient and automated exploration of molecular chemical space. Originally developed in Pracht et al. [Phys. Chem. Chem. Phys. 22, 7169 (2020)] as an automated driver for calculations at the extended tight-binding level (xTB), it offers a variety of molecular- and metadynamics simulations, geometry optimization, and molecular structure analysis capabilities. Implemented algorithms include automated procedures for conformational sampling, explicit solvation studies, the calculation of absolute molecular entropy, and the identification of molecular protonation and deprotonation sites. Calculations are set up to run concurrently, providing efficient single-node parallelization. CREST is designed to require minimal user input and comes with an implementation of the GFNn-xTB Hamiltonians and the GFN-FF force-field. Furthermore, interfaces to any quantum chemistry and force-field software can easily be created. In this article, we present recent developments in the CREST code and show a selection of applications for the most important features of the program. An important novelty is the refactored calculation backend, which provides significant speed-up for sampling of small or medium-sized drug molecules and allows for more sophisticated setups, for example, quantum mechanics/molecular mechanics and minimum energy crossing point calculations.

Calculating high-pressure vibrational frequencies analytically with the extended hydrostatic compression force field approach.

We report the implementation of the analytical Hessian for the mechanochemical extended hydrostatic compression force field method in the Q-Chem program package. To verify the implementation, the analytical Hessian was compared with finite difference calculations. In addition, we calculated the pressure dependency of the Raman active vibrational modes of methane, ethane, and hydrogen, as well as all IR and Raman active modes of Buckminsterfullerene, and compared the results with experimental and theoretical data. Our implementation paves the way for the analysis of geometric points on a pressure-deformed potential energy surface and provides a straightforward model to calculate the vibrational properties of molecules under high pressure.

Photo-ionization initiated differential ultrafast charge migration: impacts of molecular symmetries and tautomeric forms.

Photo-ionization induced ultrafast electron dynamics is considered as a precursor for the slower nuclear dynamics associated with molecular dissociation. Here, using the ab initio multielectron wave-packet propagation method, we study the overall many-electron dynamics, triggered by ionizing the outer-valence orbitals of different tautomers for a prototype molecule with more than one symmetry element. From the time evolution of the initially created averaged hole density of each system, we identify distinctly different charge dynamics responses in the tautomers. We observe that the keto form shows a charge migration direction away from the nitrogen bonded with hydrogen, while in enol-U - away from oxygen bonded to hydrogen. Additionally, the dynamics following the ionization of molecular orbitals with different symmetries reveals that a' orbitals show a fast and highly delocalized charge density in comparison to a'' symmetry. These observations indicate why different tautomers respond differently to an XUV ionization, and might explain the subsequent different fragmentation pathways. An experimental schematics allowing the detection and reconstruction of such charge dynamics is also proposed. Although the present study uses a simple, prototypical bio-relevant molecule, it reveals the explicit role of molecular symmetry and tautomerism in the ionization-triggered charge migration that controls many ultrafast physical, chemical, and biological processes, making tautomeric forms a promising tool of molecular design for desired charge migration.

Trapping the Transition State in a [2,3]-Sigmatropic Rearrangement by Applying Pressure.

Transition states are of central importance in chemistry. While they are, by definition, transient species, it has been shown before that it is possible to "trap" transition states by applying stretching forces. We here demonstrate that the task of transforming the transition state of a chemical reaction into a minimum on the potential energy surface can be achieved using hydrostatic pressure. We apply the computational extended hydrostatic compression force field (X-HCFF) approach to the educt of a [2,3]-sigmatropic rearrangement in both static and dynamic calculations and find that the five-membered cyclic transition state of this reaction becomes a minimum at pressures in the range between 100 and 150 GPa. Born-Oppenheimer molecular dynamics (BOMD) simulations suggest that slow decompression leads to a 70:30 mix of the product and the educt of the sigmatropic rearrangement. Our findings are discussed in terms of geometric parameters and electronic rearrangements throughout the reaction. To provide reference data for experimental investigations, we simulated the IR, Raman, and time-resolved UV/vis absorption spectra for the educt, transition state, and product. We speculate that the trapping of transition states by using pressure is generally possible if the transition state of a chemical reaction has a more condensed geometry than both the educt and the product, which paves the way for new ways of initiating chemical reactions.

An efficient implementation of the GOSTSHYP pressure model by applying shell-bounding Gaussian 1-electron-3-center integral screening.

We implemented a screening algorithm for one-electron-three-center overlap integrals over contracted Gaussian-type orbitals into the Q-Chem program package. The respective bounds were derived using shell-bounding Gaussians and the Obara-Saika recurrence relations. Using integral screening, we reduced the computational scaling of the Gaussians On Surface Tesserae Simulate HYdrostatic Pressure (GOSTSHYP) model in terms of calculation time and memory usage to a linear relationship with the tesserae used to discretize the surface area. Further code improvements allowed for additional performance boosts. To demonstrate the algorithm's better performance, we calculated the compressibility of fullerenes up to C180, where we were originally limited to C40 due to the high RAM usage of GOSTSHYP.

Severe Toxic Epidermal Necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms Overlap Syndrome Treated with Benralizumab: A Case Report.

TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidities in critically ill patients in intensive care units. The existing therapy for the two conditions is also a major challenge for the treating team. A possible alternative, especially for refractory cases, is benralizumab as an IL-5-receptor alpha-chain-specific humanized monoclonal antibody (IgG1k). We are able to show a successful treatment in this case report.

Can a Finite Chain of Hydrogen Cyanide Molecules Model a Crystal?

When calculating structural or spectroscopic properties of molecular crystals, the question arises whether it is sufficient to simulate only a single molecule or a small molecular cluster or whether the simulation of the entire crystal is indispensable. In this work we juxtapose calculations on the high-pressure structural properties of the (periodic) HCN crystal and chains of HCN molecules of finite length. We find that, in most cases, the behavior of the crystal can be reproduced by computational methods simulating only around 15 molecules. The pressure-induced lengthening of the C-H bond in HCN found in calculations on both the periodic and finite material are explained in terms of orbital interaction. Our results pave the way for a more thorough understanding of high-pressure structural properties of materials and give incentives for the design of materials that expand under pressure. In addition, they shed light on the complementarity between calculations on periodic materials and systems of finite size.

A Two-Step Baromechanical Cycle for Repeated Activation and Deactivation of Mechanophores.

Mechanophores that are embedded in a polymer backbone respond to the application of mechanical stretching forces by geometric changes such as bond rupture. Typically, these structural changes are irreversible, which limits the applicability of functional materials incorporating mechanophores. Using computational methods, we, here, present a general method of restoring a force-activated mechanophore to its deactivated form by using hydrostatic pressure. We use the spiropyran-merocyanine (SP-MC) interconversion to show that repeated activation of the SP mechanophore and deactivation of MC can be achieved by alternating mechanical stretching and hydrostatic compression, respectively. In the baromechanical cycle, MC acts as a "barophore" that responds to hydrostatic pressure by bond formation. The activation and deactivation of SP/MC are understood in terms of strain and electronic effects. Beneficially, this two-step baromechanical cycle can be observed in real time by using UV/vis spectroscopy. Our calculations pave the way for improving the applicability and reusability of force-responsive materials.