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

Abstract

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.

Calculation of absolute molecular entropies and heat capacities made simple

“…S msRRHO,ref typically refers to the DFT reference structure, for which vibrational frequencies are calculated at the SQM or FF level. To avoid changes to the geometry and appearance of imaginary vibrational modes, we here additionally make use of a new procedure called Single Point Hessian (SPH), 59,60 for which some details are given in the ESI. † Note that if S msRRHO is calculated at the same level as S msRRHO , one would arrive at the correct population average because S msRRHO and S msRRHO,ref exactly cancel each other.…”

Automated exploration of the low-energy chemical space with fast quantum chemical methods

“…20,21 Efficient algorithms and powerful processing units (CPUs, GPUs) are nowadays able to perform QM calculations on standard desktop computers. [22][23][24][25] However, Moor's law of technological advance, 26 which has been in act for over half a century, is beginning to falter and it is expected that silicon-based computing capacities reach their physical limitations by the end of the 1. Introduction decade.…”

“…In a more general perspective, they may be used in combination with CREST for initial stages of a computational project where thousands of structures have to be evaluated and automatization is highly beneficial. This may provide the basis for "bottom-up" screening procedures 22,40 that result in accurate molecular property predictions calculated with high level electronic structure methods (cf. .…”

A Robust and Efficient Implicit Solvation Model for Fast Semiempirical Methods

“…For conformational changes, the solvent accessibility of the polar groups in the solute as well as the SASA may change drastically and hence solvation effects can be crucial for the relative energetic ordering in conformational ensembles. As an example, the PES of the antibiotic drug erythromycin was investigated using the recently developed CRENSO 86 workflow with a final conformational energy threshold of 3.0 kcal/mol. The resulting optimized structure ensemble consists of six conformers within this energy window.…”

“…the PES of the antibiotic drug erythromycin was investigated using the recently developed CRENSO86 workflow with a final conformational energy threshold of 3.0 kcal/mol. The resulting optimized structure ensemble consists of six conformers within this energy window.…”