Positional Variance in NMR Crystallography.

Area of Science:

• Solid-state Nuclear Magnetic Resonance (NMR) Spectroscopy
• Crystallography
• Computational Chemistry

Background:

• Chemical-shift-based NMR crystallography is a powerful technique for determining crystal structures.
• Quantifying positional uncertainties is crucial for understanding the reliability of these structures.
• Existing methods for uncertainty quantification in NMR crystallography are limited.

Purpose of the Study:

• To develop and validate a novel method for quantifying positional uncertainties in crystal structures determined by NMR crystallography.
• To assess both average and atom-specific positional accuracy (isotropic and anisotropic).
• To compare the accuracy of NMR crystallography with single-crystal X-ray diffraction.

Main Methods:

• Combining molecular dynamics (MD) simulations with density functional theory (DFT) calculations.
• Incorporating experimental and computational chemical shift uncertainties.
• Applying the method to diverse organic crystal structures, including pharmaceuticals.

Main Results:

• The developed method successfully quantifies average and atom-specific positional uncertainties.
• Demonstrated on crystal structures of cocaine, flutamide, flufenamic acid, penicillin G K salt, and AZD8329.
• For cocaine, the positional Root Mean Square Deviation (RMSD) uncertainty was 0.17 Å.

Conclusions:

• The proposed method provides a robust way to assess positional accuracy in NMR crystallography.
• NMR crystallography, using this uncertainty quantification, achieves higher positional accuracy than X-ray diffraction.
• This advancement enhances the reliability and utility of NMR crystallography for structure determination.