Allowed conformations for protonated and unprotonated lidocaine: three-dimensional isopotential energy surfaces

Abstract

The conformational energies of unprotonated and protonated lidocaine were calculated using nonbonded, electrostatic, and torsional potential energy functions. Calculations were performed varying three central torsion angles in the molecules from 0 to 360° at 10° intervals. The results of the energy calculations were represented as three-dimensional isopotential energy surfaces from which the regions of low-energy conformations allowed for each molecule could be selected. Each of these calculations was repeated as a fourth dihedral angle was varied in increments of 20° between 0 and 360°. In this manner, a global minimum was found for unprotonated and for protonated lidocaine. A comparison of the three-dimensional isopotential energy surfaces for unprotonated lidocaine with that of protonated lidocaine shows a striking difference for the global minimum for the N–CO–CH₂–N dihedral angle. The angle is near 70° for unprotonated lidocaine and 220° for protonated lidocaine, resulting in a more extended structure for the protonated molecule. The three-dimensional isopotential surfaces also reveal that the conformational freedom allowed for lidocaine is greatly reduced when it is protonated. The difference in the electrostatic interaction between the two forms of lidocaine is responsible for the large differences in conformational preference. The threedimensional isopotential energy surfaces suggest minimum-energy pathways by which the molecules may interconvert from one to another low-energy conformational region.