QM/MM refinement and analysis of protein bound retinoic acid

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. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2012