Calculated conformer energies for organic molecules with multiple polar functionalities are method dependent: Taxol...

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Drug Discovery

Background:

• Molecular mechanics (MM) and quantum chemical (QM) calculations are essential for studying molecular stereochemistry and conformation.
• These computational methods have been widely used to investigate the conformational profile of Taxol, both in solution and within the beta-tubulin protein binding site.

Purpose of the Study:

• To compare the relative energies of seven Taxol conformations, derived from NMR and X-ray data, using various MM and semiempirical QM methods.
• To evaluate the accuracy of these computational methods in predicting experimental conformational preferences for Taxol.

Main Methods:

• Utilized a set of widely employed force fields and semiempirical molecular orbital (MO) methods.
• Applied a continuum solvent treatment in conjunction with the computational methods.
• Compared calculated relative conformational energies against experimental data from NMR and X-ray analyses.

Main Results:

• Significant divergence was observed among the computational procedures in assessing the relative conformational energies of Taxol.
• None of the tested MM or semiempirical QM methods provided satisfactory agreement with experimental findings.
• The methods failed to consistently rank the side-chain conformations of Taxol energetically.

Conclusions:

• Molecular mechanics and semiempirical QM methods are inadequate for reliably determining the energetic ranking of Taxol side-chain conformations.
• For highly polar organic structures like Taxol, "energy-free" conformational search methods are advised for more accurate results.