Unphysical Structure Collapse in Quantum Mechanics Calculations With Continuum Solvation.

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Polarizable continuum models (PCMs) like CPCM and SMD are widely used for solvation.
• Accurate prediction of molecular conformations is crucial for drug design.

Purpose of the Study:

• To evaluate the performance of CPCM and SMD models in describing the conformational energies of drug-like molecules.
• To compare computational predictions with experimental data (NMR) and explicit solvation simulations.

Main Methods:

• Quantum mechanics (QM)-based CREST workflow and OPLS4 force-field simulations (MCMM) were used for conformer ensemble generation.
• Conformations were optimized using r2SCAN-3c and r2SCAN-d3(BJ)/aug-cc-pVTZ.
• Generalized-Born/surface-area (GB/SA) continuum solvent model was employed.
• 1D/2D NMR experiments (NOESY) and explicit solvation molecular dynamics simulations were performed.

Main Results:

• QM and OPLS4/CPCM methods predominantly yielded collapsed π-stacking conformations.
• OPLS4/GB/SA simulations resulted in stretched conformations.
• NMR experiments and explicit solvation simulations indicated minimal (<5%) collapsed conformations.

Conclusions:

• Standard PCM implementations do not accurately represent solvent interactions (specific, directed) and neglect entropic contributions.
• Continuum solvation models lead to unphysical conformational ensembles for the studied molecules.
• More sophisticated solvation models are needed for accurate conformational analysis.