Efficient Quantum Chemical Calculation of Structure Ensembles and Free Energies for Nonrigid Molecules

The application of quantum chemical, automatic multilevel modeling workflows for the determination of thermodynamic (e.g., conformation equilibria, partition coefficients, pK a values) and spectroscopic properties of relatively large, nonrigid molecules in solution is described. Key points are the computation of rather complete structure (conformer) ensembles with extremely fast but still reasonable GFN2-xTB or GFN-FF semiempirical methods in the CREST searching approach and subsequent refinement at a recently developed, accurate r(2)SCAN-3c DFT composite level. Solvation effects are included in all steps by accurate continuum solvation models (ALPB, (D)COSMO-RS). Consistent inclusion of thermostatistical contributions in the framework of the modified rigid-rotor-harmonic-oscillator approximation (mRRHO) based on xTB/FF computed PES is also recommended.

Automated summary

The study demonstrates the use of quantum chemical and automatic multilevel modeling workflows for determining thermodynamic and spectroscopic properties of relatively large, nonrigid molecules in solution. Key aspects include generating structure ensembles with fast but reasonable methods and refining them at a high level of accuracy.