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QM/MM refinement and analysis of protein bound retinoic acid.

ABSTRACT: Retinoic acid (RA) is a vitamin A derivative, which modifies the appearance of fine wrinkles and roughness of facial skin and treats acne and activates gene transcription by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoic X receptor (RXR). There are series of protein bound RA complexes available in the protein databank (PDB), which provides a broad range of information about the different bioactive conformations of RA. To gain further insights into the observed bioactive RA conformations we applied quantum mechanic (QM)/molecular mechanic (MM) approaches to re-refine the available RA protein-ligand complexes. MP2 complete basis set (CBS) extrapolations single energy calculations are also carried out for both the experimental conformations and QM optimized geometries of RA in the gas as well as solution phase. The results demonstrate that the re-refined structures show better geometries for RA than seen in the originally deposited PDB structures through the use of QMs for the ligand in the X-ray refinement procedure. QM/MM re-refined conformations also reduced the computed strain energies found in the deposited crystal conformations for RA. Finally, the dependence of ligand strain on resolution is analyzed. It is shown that ligand strain is not converged in our calculations and is likely an artifact of the typical resolutions employed to study protein-ligand complexes.

SUBMITTER: Li X

PROVIDER: S-EPMC3240731 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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QM/MM refinement and analysis of protein bound retinoic acid.

Li Xue X Fu Zheng Z Merz Kenneth M KM

Journal of computational chemistry 20111123 3

Retinoic acid (RA) is a vitamin A derivative, which modifies the appearance of fine wrinkles and roughness of facial skin and treats acne and activates gene transcription by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoic X receptor (RXR). There are series of protein bound RA complexes available in the protein databank (PDB), which provides a broad range of information about the different bioactive conformations of RA. To gain further insights into the observed bioac ...[more]

PMID: 22108894

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Project description: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 Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method-coupled with our XModeScore method for experimental tautomer/protomer state determination-to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields.

Dataset Information

QM/MM refinement and analysis of protein bound retinoic acid.

Publications

QM/MM refinement and analysis of protein bound retinoic acid.

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