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.

Reliable prediction of association (free) energies of supramolecular complexes with heavy main group elements - the HS13L benchmark set.

We introduce a set of 13 supramolecular complexes featuring diverse non-covalent interactions with heavy main group elements (Zn, As, Se, Te, Br, I), high charges (-2 up to +4), and large systems with up to 266 atoms (HS13L). The experimental Gibbs free energies of association cover the typical range (-1.9 to -9.2 kcal mol-1). An efficient automated multilevel theoretical workflow is applied for the determination of the respective minimum structures in solution by conformer ensemble generation with the CREST program at the semiempirical GFN2-xTB level. Subsequent refinement is performed with the r2SCAN-3c composite DFT method including thermostatistical corrections at the GFN2-xTB level and solvation contributions by COSMO-RS using the CENSO free energy ranking algorithm. Various density functional approximations in combination with three London dispersion correction schemes are assessed against "back-corrected" experimental association energies as well as accurate local coupled cluster reference values. Our protocol predicts association free energies with a mean absolute deviation of only 2 kcal mol-1 from the measured values. Thus, it is well suited to generate reference association free energies for assessing theoretical methods on realistically sized supramolecular complexes or to support experimental chemists. For specifically evaluating methods for calculating gas-phase association energies, we recommend using the provided accurate coupled cluster reference values. We propose to use this set as an extension of the S30L benchmark set [Sure et al., J. Chem. Theory Comput., 2015, 11, 3785-3801] with a special focus on the challenging computation of non-covalent interactions of heavy main group elements.

Towards understanding solvation effects on the conformational entropy of non-rigid molecules.

The absolute molecular entropy is a fundamental quantity for the accurate description of thermodynamic properties. For non-rigid molecules, a substantial part of the entropy can be attributed to a conformational contribution. Systems and properties where this is relevant, e.g., protein-ligand binding affinities or pKa values refer usually to the liquid phase. In this work, the influence of solvation on the conformational entropy is investigated. A recently introduced state-of-the-art and automated computational protocol for the computation of conformational entropies [Pracht et al., Chem. Sci., 2021, 12, 6551-6568.] is applied in combination with fast and accurate semiempirical quantum-chemical methods and implicit solvation models for a set of 25 commercially available drug molecules and five transition metal compounds. Computed gas-phase conformational entropies are compared with values obtained in implicit n-hexane and water. It is found that implicit solvation can have a substantial effect of several cal mol-1 K-1 on the entropy as a result of large conformational changes in the different phases. We conclude that for flexible molecules chemical accuracy for free energies in solution can only be achieved if solvation effects on the conformational ensemble are considered.