The critical role of QM/MM X-ray refinement and accurate tautomer/protomer determination in structure-based drug design.

ABSTRACT: Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule-along with any bound ligand(s)-within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Su

SUBMITTER: Borbulevych OY 

PROVIDER: S-EPMC8018927 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature