CONFORMATIONAL FLEXIBILITY OF O-PHOSPHORYLCHOLINE AND O-PHOSPHORYLETHANOLAMINE - A MOLECULAR-DYNAMICS STUDY OF SOLVATION EFFECTS

The influence of solvent on the conformational flexibility of o-phosph orylcholine, CH3PO4-CH2CH2N(CH3)(3)(+), and of o-phosphorylethanolamin e, CH3PO4-CH2CH2NH3+, model compounds for the two most common phosphol ipid headgroups (PC and PE), was explored using molecular dynamics cal culations based on a microscopic model with full atomic details. The p otential of mean force about the principal dihedral angle, O-C-C-N, wa s calculated for the model compounds in vacuum and in bulk water using the umbrella sampling technique. Tn vacuum, the trans conformation is unstable and strongly disfavored with respect to the gauche conformat ion due to the loss of intramolecular electrostatic interactions. In b ulk water, the influence of solvent results in a stabilization of the trans conformation yielding trans/ gauche energy differences of +1.5 a nd +0.02 kcal/mol for the model compounds of PC and PE, respectively. This result is in qualitative agreement with experimental NMR estimate s from an analysis based on J-coupling constants due to Akutsu and Kyo goku (Chem. Phys. Lipids 1977, 18, 285-303) and Hauser (Biochemistry 1 980, 19, 366-373). To further understand the nature of solvation effec ts, the dihedral potential of mean force is calculated for model syste ms in which the solvent is represented, first, by a vacuum continuum d ielectric constant and, second, by a small number of explicit perimary hydration water molecules solvating the phosphate and nitrogen groups . It found empirically that a vacuum continuum dielectric constant of 80 or the presence of 20 explicit primary waters is sufficient to stab ilize the trans conformation and reproduce qualitatively the influence of bulk solvation. This suggests that the solvent-induced increased i ntramolecular conformational flexibility may be equivalently interpret ed in terms of continuum dielectric shielding or solvent structure eff ects by the primary hydration shell. The conformational flexibility of the molecules is further characterized by estimating the transition r ate constants between the stable conformations in bulk solvent.