Exploring the impact of alignment media on RDC analysis of phosphorus-containing compounds: a molecular docking approach

0581606 - ÚOCHB 2025 RIV GB eng J - Journal Article
Christou Tichotová, Markéta - Tučková, Lucie - Kocek, Hugo - Růžička, A. - Straka, Michal - Procházková, Eliška
Exploring the impact of alignment media on RDC analysis of phosphorus-containing compounds: a molecular docking approach.
Physical Chemistry Chemical Physics. Roč. 26, č. 3 (2024), s. 2016-2024. ISSN 1463-9076. E-ISSN 1463-9084
R&D Projects: GA ČR(CZ) GA21-23014S
Institutional support: RVO:61388963
Keywords : residual dipolar couplings * benzyl-L-glutamate * NMR spectroscopy
OECD category: Physical chemistry
Impact factor: 3.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1039/D3CP04099B

Residual dipolar couplings (RDCs) are employed in NMR analysis when conventional methods, such as J-couplings and nuclear Overhauser effects (NOEs) fail. Low-energy (optimized) conformers are often used as input structures in RDC analysis programs. However, these low-energy structures do not necessarily resemble conformations found in anisotropic environments due to interactions with the alignment medium, especially if the analyte molecules are flexible. Considering interactions with alignment media in RDC analysis, we developed and evaluated a molecular docking-based approach to generate more accurate conformer ensembles for compounds in the presence of the poly-gamma-benzyl-l-glutamate alignment medium. We designed chiral phosphorus-containing compounds that enabled us to utilize 31P NMR parameters for the stereochemical analysis. Using P3D/PALES software to evaluate diastereomer discrimination, we found that our conformer ensembles outperform moderately the standard, low-energy conformers in RDC analysis. To further improve our results, we (i) averaged the experimental values of the molecular docking-based conformers by applying the Boltzmann distribution and (ii) optimized the structures through normal mode relaxation, thereby enhancing the Pearson correlation factor R and even diastereomer discrimination in some cases. Nevertheless, we presume that significant differences between J-couplings in isotropic and in anisotropic environments may preclude RDC measurements for flexible molecules. Therefore, generating conformer ensembles based on molecular docking enhances RDC analysis for mildly flexible systems while flexible molecules may require applying more advanced approaches, in particular approaches including dynamical effects.
Permanent Link: https://hdl.handle.net/11104/0349708