Torsion Angle Preference and Energetics of Small-Molecule Ligands Bound to Proteins

Small organic molecules can assume conformations in the protein-bound state that are significantly different from those in solution. We have analyzed the conformations of 21 common torsion motifs of small molecules extracted from crystal structures of protein−ligand complexes and compared them with their torsion potentials calculated by an ab initio DFT method. We find a good correlation between the potential energy of the torsion motifs and their conformational distribution in the protein-bound state: The most probable conformations of the torsion motifs agree well with the calculated global energy minima, and the lowest torsion-energy state becomes increasingly dominant as the torsion barrier height increases. The torsion motifs can be divided into 3 groups based on torsion barrier heights: high (>4 kcal/mol), medium (2−4 kcal/mol), and low (95% of conformational torsions occur in the energy region