The conformational potential of the dimethyl phosphate (DMP) anion and the 2-ammonioethanol (AME) cation, which are substructures of the phosphoethanolamine head group of phospholipids, has been investigated at the Hartree-Fock (HF) level using the 3-21G, 3-21G(*), 6-31G*, and 6-31+G* basis set. For this purpose, both the DMP anion and the AME cation were considered as geminal double rotors with the two rotor groups OCH3 in the case of DMP and OH and CH2NH3+ in the case of AME. Extensive scans (17 points including eight stationary points for DMP and 30 points including seven stationary points for AME) of the conformational energy surface were carried out by complete geometry optimizations at the HF/3-21G and HF/3-21G(*) levels, respectively, and subsequent single point calculations with larger basis sets. The most stable DMP form has the two OCH3 groups in syn-clinal (+sc) positions (both dihedral angles a 2 and a 3 = 75.3') while the AME cation prefers an anti-periplanar (ap) (Q = 173.3'), syn-clinal (+sc) (a5 = 48.5') conformation with regard to the OH and CH2NH3+ groups. The DMP anion is a rather flexible rotor that can undergo various flip-flop rotations (barriers 1 and 6 kcal/mol) that indicate strong coupling between the rotor groups. The AME cation, on the other hand, is conformationally not flexible, which has to do with the fact that the two rotor groups OH and CH2NH3+ are electronically very different. The preferred rotational processes of the AME cation involve inwardly or outwardly directed rotations at the CC bond (barriers of 5.1 and 9.3 kcaymol) with the OH group kept essentially in an ap position. Calculations reveal that semiempirical methods such as PM3 are not able to describe the conformational tendencies of either DMP anion or AME cation correctly.

The effect of the polarity of the environment on the conformation of the zwitterionic membrane lipid head groups phosphoethanolamine (PE) and phosphocholine (PC) has been investigated with calculations at the Hartree-Fock level using the 3-21G(*), 6-31G*, and 6-31+G* basis sets together with the Onsager continuum solvation model. Results suggest that in the gas phase both PE and PC adopt cyclic minimum energy conformations, in which an ammonium or N-methyl hydrogen closely approaches one of the nonesterified phosphate oxygens. In the case of PE, intramolecular interactions result in a proton transfer from the ammonium group to the phosphate oxygen, which however is suppressed by a moderate increase in the polarity of the surrounding medium. With increasing polarity of the environment, the cyclic structures of PE and PC still remain low-energy conformers but simultaneously for both head groups an almost identical extended conformer, typical of crystal structures, becomes increasingly favored. Already at ) 10, the extended conformer of PC is favored (-2.4 kcal/mol) relative to the cyclic one, while for PE the relative energy of the extended conformer approaches that of the cyclic one at ) 80. The similarity and increasing stability of the extended PE/PC conformers in the monomeric state and the fact that this conformer is also adopted in all crystal structures of PE/PC lipids, regardless of hydration and interaction pattern, indicate that the geometry of this conformer is determined by energetics intrinsic to the phosphoethanolammonium backbone. In lipid aggregates or a membrane environment the extended conformer becomes additionally stabilized by intermolecular ionic and hydrogen bond interactions with neighboring molecules substituting for the internal interaction that in the monomeric state constrains the zwitterionic dipole into a cyclic structure.