Benchmarking quantum chemical methods with X-ray structures via structure-specific restraints

Area of Science:

• Solid-state chemistry
• Computational chemistry
• Crystallography

Background:

• Pharmaceutical research requires accurate crystal structure optimization for property prediction.
• Experimental crystal structures often need augmentation to a consistent quality level.
• Increasing molecular size and complexity necessitate efficient computational methods.

Purpose of the Study:

• To evaluate the accuracy and efficiency of molecule-in-cluster (MIC) computations for solid-state structure optimization.
• To compare MIC computations against full-periodic (FP) calculations for augmenting experimental crystal structures.
• To assess the impact of different quantum mechanical methods and basis sets within the MIC framework.

Main Methods:

• Utilized molecule-in-cluster (MIC) computations within a quantum mechanics/molecular mechanics (QM:MM) framework.
• Assessed selected quantum mechanical methods, including DFT-D and GFN2-xTB.
• Employed crystallographic least-squares refinements with computed structure-specific restraints and compared root mean square Cartesian displacements.

Main Results:

• MIC DFT-D QM:MM computations yielded improved restraints and coordinates compared to MIC GFN2-xTB.
• Increasing the quantum mechanical basis set size in MIC QM:MM did not consistently enhance results.
• The choice of DFT functional was less critical than the basis set selection for accuracy.

Conclusions:

• MIC computations provide an accurate and computationally efficient alternative to full-periodic calculations for solid-state structure optimization.
• MIC methods are suitable for augmenting experimental crystal structures, especially those with disorder or multiple molecules.
• This approach facilitates high-quality comparative studies and property predictions in pharmaceutical research.