Towards The Chemical Synthesis Of A Voltage Gated K+ Channel

Abstract

Understanding the relationship between the atomic structure of a protein and the biological functions requires the ability to perturb the protein structure in a precise manner. This is generally accomplished by means of traditional site-directed mutagenesis. However, the modifications that can be introduced in this manner are limited by the set of naturally occurring amino acids. Chemical synthesis on the other hand facilitates the incorporation of a wide variety of side chain and peptide backbone modifications that enables precise modifications of the structural and electronic properties of the protein. Similar modifications are not possible using conventional mutagenesis, thus making chemical synthesis an important asset in investigations of protein structure and function. The size of the protein has been a major factor limiting the use of chemical synthesis to investigate proteins. In the field of membrane proteins, chemical synthesis has so far been accomplished only for relatively small ( 150 amino acid) membrane proteins are required. We are presently developing methodology for the chemical synthesis of the voltage gated K+ channel KvAP. Voltage gated ion channels are responsible for the generation of electrical impulses by excitable cells. They have been the subject of intense research, however, a number of key questions remain about the mechanisms of ionic selectivity and gating in these channels. We believe that using chemical synthesis for protein modification in combination with functional and structural studies will enable us to provide new information on these physiologically important processes.