Unphysical Structure Collapse in Quantum Mechanics Calculations With Continuum Solvation.

The work reports on issues of the polarizable continuum solvent models conductor-like polarizable continuum model (CPCM) and solvation model density (SMD) to adequately describe the relative conformer energies of drug-like molecules that fit the quite common general structural pattern of two aromatic segments connected by a flexible linker. Conformer ensembles derived either from a quantum mechanics (QM)-based CREST workflow or from optimized potentials for liquid simulations (OPLS4) force-field based macromodel Monte Carlo multiple minimum (MCMM) torsional sampling, after r2SCAN-3c optimization and r2SCAN-d3(BJ)/aug-cc-pVTZ result exclusively in collapsed π-stacking conformations. OPLS4 optimizations with generalized-Born/surface-area (GB/SA) continuum solvent model result almost exclusively in semistretched and stretched conformations. 1D and 2D nuclear magnetic resonance (NMR) experiments, on the other hand, clearly show no hydrogen-shielding nor any other hints for the occurrence of collapsed conformations under various NOESY conditions. Explicit solvation molecular dynamics simulations are consistent with NMR experiments in that they reveal maximally about 5% population of collapsed conformations in explicit water and 0.2% in DMSO. We conclude that PCM as implemented in all major quantum chemistry codes does not reflect the real nature of solvents consisting of molecules with specific and directed solvent-solvent and solvent-solute interactions and in addition missing entropic contributions and by this continuum solvation contributions result in unphysical conformational ensembles.