Cellular functions are carried out by protein molecules, which assume folded shapes, determined by the linear sequences of their amino acid residues. Understanding how the folded, functional shape of a native protein is encoded in the linear sequence of its amino acids has been termed the second genetic code. Much is now known about this code, but major problems are still unsolved. This proposal aims at a predictive understanding of two intrinsic features of folding, formation of secondary structure and tertiary packing, for the important case of peptide helices. Amino acids that are sequence neighbors form secondary structures helices, sheets or turns, and these pack to form the compact global tertiary structure of a functional protein. This project works with peptides, which are regions of proteins, prepared by synthesis.
Its aim i s a predictive, quantitative correlation between peptide helicity and its amino acid composition and sequence. Initial algorithm construction will be based on a recent result that permits polyalanines to be used as hosts for quantitating the effects of replacing alanine residues by other amino acids. Peptide helicity will be studied by CD, which measures helicity, and NMR, which can provide detailed information concerning helical structure and provide two types of independent measures of helicity. These will be applied to synthetic peptides to model simple helices in water and dimeric helical coiled coils of the leucine zipper type. The latter are the simplest examples of protein structures that embody the compactness and structural integrity of a typical protein. Helical sections of proteins are involved in recognition steps key to the pathology of important human disease states, and highly helical protein fragments, polypeptides are potentially very useful tools for studying the cascade of events that attend these cellular signaling processes. Oncogenes that control human tumors often are regulated by helix-oligonucleotide interactions. Superstable peptide helices developed in this project are likely to generate diagnostic tools and possibly tissue-targeted drug delivery agents.
