Electrostatic Interactions in Chemistry and Biology

Electrostatic interactions such as hydrogen bonds, salt bridges, and cation-π interactions play a large role in structural biology. A major goal of this thesis is to build upon previous studies of the cation-1r interaction to further understand its role in biological systems. Put simply, we wish to understand how, when, and why Nature uses cation-π interactions. We begin by highlighting a cation-1r interaction important in the binding of acetylcholine to the nicotinic acetylcholine receptor (nAChR). By combining ab initio calculations and molecular neurobiology, we provide compelling evidence that a cation-π interaction is a major determinant of the recognition of acetylcholine by the nAChR. We then ask a broader question: To what extent does Nature use cation-π interactions within protein structures? By surveying the protein databank, we demonstrate that energetically significant cation-π interactions are quite common within protein structures. To explain why, we ask what advantages cation-π interactions have over other noncovalent interactions commonly found in proteins. Using quantum mechanical calculations, we study the strengths of cation-π interactions and salt bridges in both water and in a range of organic solvents. The results suggest that cation-π interactions maintain their strength over a wide range of solvents, whereas the strength of a salt bridge is severely attenuated when it is placed in a high-dielectric solvent. We then turn our attention to a different type of electrostatic interaction - the interaction between water and hexafluorobenzene. We find that in the gas phase, water binds to hexafluorobenzene in a geometry in which the lone pairs of electrons located on the oxygen are directed towards the π-system of the aromatic. This surprising result is easily explained using electrostatics. In addition, we present computational studies of the triphenylene···perfluorotriphenylene "supramolecular synthon." Finally, we return to the nAChR. A challenge in the study of integral membrane proteins is determining their transmembrane topology. Here we present a potentially general method for determining not only the transmembrane topology of a functional neuroreceptor expressed in a living cell, but also the surface accessibility of individual amino acids.