The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. 66 all-trans-RA and 48 9-cis-RA energy minimum conformers were identified using HF/6-31G* geometry optimization in vacuo. Their relative conformational energies were estimated by means of M06, M062x and MP2 level of theories combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets and MP2/CBS extrapolations using the latter two basis sets. We also used previously reported  QM/MM X-ray refinement results on five RA-protein crystal structures in order to investigate the conformational preferences of bound retinoic acid. An average 91.3% reduction of local strain energy in the gas phase as well as 92.1% in PCM solvent were observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of crystal structures refined by conventional refinement protocols.

Conformational analysis of free and bound retinoic acid

243rd National Meeting (2012)

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