The effect of solvation on biomolecular conformation: 2-amino-1-phenylethanol.

Small molecule neurotransmitters form one the most important classes of pharmaceutical molecules. While the behavior of these molecules in their neutral forms in the gas phase is well understood, their behavior in more biologically relevant scenarios (protonated and in aqueous solution) has received comparatively little attention. Here we address this problem by using molecular mechanics simulations to build up a detailed picture of the conformational behavior of 2-amino-1-phenylethanol, a noradrenaline analogue, in aqueous solution in both its neutral and protonated forms. For the sake of comparison, equivalent simulations are also performed on the gas-phase molecules and gas-phase hydrated clusters. These calculations reveal the important role that water has to play in determining the conformational preferences and dynamic behavior of the molecules. Water molecules are found to bridge between the various functional groups within the molecule, significantly affecting their relative stabilities in comparison to the gas-phase values. The reorganization of these solvation structures also provides a mechanism for conformational interconversion. The role of the solvent in mediating interactions between the various functional groups within the molecule suggests that in noradrenaline the catechol groups will be able to interact, albeit indirectly, with the other functional groups, thereby influencing the behavior of the molecule.