**CREST—A Program for the Exploration of Low-Energy Molecular Chemical Space** **Authors:** Philipp Pracht, Stefan Grimme, Christoph Bannwarth, Fabian Bohle, Sebastian Ehler, Geroen Feldmann, Johannes Gorges, Marcel Müller, Tim Neudecker, Christoph Plett, Sebastian Spicher, Pit Steinbach, Patryk A. Wesolowski, Felix Zeller **Journal:** J. Chem. Phys. 160, 114110 (2024) **DOI:** 10.1063/5.0197592 **Abstract:** Conformer–rotamer sampling tool (CREST) is an open-source program designed for efficient and automated exploration of molecular chemical space. Originally developed as an automated driver for calculations at the extended tight-binding level (xTB), CREST offers a variety of capabilities including molecular and metadynamics simulations, geometry optimization, and molecular structure analysis. The program includes automated procedures for conformational sampling, explicit solvation studies, absolute molecular entropy calculation, and identification of 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 includes implementations of GFNn-xTB Hamiltonians and the GFN-FF force field. Recent developments in CREST include a refactored calculation backend that significantly improves performance for small to medium-sized drug molecules and allows for more sophisticated setups, such as quantum mechanics/molecular mechanics and minimum energy crossing point calculations. **Key Features:** 1. **Conformational Sampling:** CREST uses a metadynamics-based algorithm for conformational sampling, which is automated and can handle a wide range of systems. 2. **Explicit Solvation Studies:** The Quantum Cluster Growth (QCG) algorithm allows for the automated generation of cluster ensembles containing solute-solvent interactions, enabling explicit solvation studies. 3. **Absolute Molecular Entropy Calculation:** An algorithm for calculating absolute molecular entropy based on quasi-harmonic analysis (QHA) is implemented, providing accurate thermodynamic properties. 4. **Protonation and Deprotonation Site Identification:** Localized molecular orbitals (LMOs) from GFNn-xTB can be used to identify possible protonation and deprotonation sites, facilitating the calculation of prototropic tautomers. **Applications:** - **Conformational Sampling:** CREST is particularly useful for exploring the conformational space of drug-sized molecules, providing robust and efficient sampling. - **Explicit Solvation:** The QCG algorithm can model explicit and micro-solvation, making it suitable for studying solute-solvent interactions. - **Absolute Molecular Entropy:** The calculated entropy is crucial for accurate thermodynamic properties, such as Gibbs free energy. - **Protonation and Deprotonation**CREST—A Program for the Exploration of Low-Energy Molecular Chemical Space** **Authors:** Philipp Pracht, Stefan Grimme, Christoph Bannwarth, Fabian Bohle, Sebastian Ehler, Geroen Feldmann, Johannes Gorges, Marcel Müller, Tim Neudecker, Christoph Plett, Sebastian Spicher, Pit Steinbach, Patryk A. Wesolowski, Felix Zeller **Journal:** J. Chem. Phys. 160, 114110 (2024) **DOI:** 10.1063/5.0197592 **Abstract:** Conformer–rotamer sampling tool (CREST) is an open-source program designed for efficient and automated exploration of molecular chemical space. Originally developed as an automated driver for calculations at the extended tight-binding level (xTB), CREST offers a variety of capabilities including molecular and metadynamics simulations, geometry optimization, and molecular structure analysis. The program includes automated procedures for conformational sampling, explicit solvation studies, absolute molecular entropy calculation, and identification of 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 includes implementations of GFNn-xTB Hamiltonians and the GFN-FF force field. Recent developments in CREST include a refactored calculation backend that significantly improves performance for small to medium-sized drug molecules and allows for more sophisticated setups, such as quantum mechanics/molecular mechanics and minimum energy crossing point calculations. **Key Features:** 1. **Conformational Sampling:** CREST uses a metadynamics-based algorithm for conformational sampling, which is automated and can handle a wide range of systems. 2. **Explicit Solvation Studies:** The Quantum Cluster Growth (QCG) algorithm allows for the automated generation of cluster ensembles containing solute-solvent interactions, enabling explicit solvation studies. 3. **Absolute Molecular Entropy Calculation:** An algorithm for calculating absolute molecular entropy based on quasi-harmonic analysis (QHA) is implemented, providing accurate thermodynamic properties. 4. **Protonation and Deprotonation Site Identification:** Localized molecular orbitals (LMOs) from GFNn-xTB can be used to identify possible protonation and deprotonation sites, facilitating the calculation of prototropic tautomers. **Applications:** - **Conformational Sampling:** CREST is particularly useful for exploring the conformational space of drug-sized molecules, providing robust and efficient sampling. - **Explicit Solvation:** The QCG algorithm can model explicit and micro-solvation, making it suitable for studying solute-solvent interactions. - **Absolute Molecular Entropy:** The calculated entropy is crucial for accurate thermodynamic properties, such as Gibbs free energy. - **Protonation and Deprotonation