For Biophysics Week, members of the Publications Committee selected a few influential articles from Biophysical Journal to highlight as well as the people who wrote them. This is the second in the series.
Written by Publications Committee member Shriyaa Mittal, University of Illinois at Urbana-Champaign
Biophysicists who study protein molecules use helical wheels regularly. Helical wheels are a standard way to predict protein sequence segments with either helical or non-helical potential. These diagrams are projections of a protein's amino acid sequence onto a plane perpendicular to the axis of the helix. The perimeter of the wheel corresponds to the protein's backbone and the external spokes to the side chains.
Helical wheels were first described in an article published in the Biophysical Journal in 1967, “Use of Helical Wheels to Represent the Structures of Proteins and to Identify Segments with Helical Potential.” (1) The US Atomic Energy Commission, which dissolved in 1975, supported this work.
To find out more, Shriyaa Mittal asked Dr. Marianne Schiffer, lead author on the Biophysical Journal article, about her recollections of this work. Dr. Schiffer is now an Emeritus scientist at Argonne National Laboratory.
Before Dr. Schiffer looked into her notes from 1965–1966 in order to remember things beyond having a one-year old baby, she recalled it being an exciting time. In the fall of 1965, she started working as a postdoc at Argonne with Dr. Allen Edmundson. At that time, the very first three-dimensional structures of proteins had been determined, illuminating the molecular architecture of myoglobin and lysozyme.
Dr. Schiffer writes, “Edmundson, a protein chemist, had determined the amino acid sequence of myoglobin and was interested in understanding its three-dimensional structure. My background was in X-ray crystallography, hence I could visualize structures in three dimensions and understand projections to two dimensions.” Helical wheels are also referred to as “Schiffer-Edmundsun wheels” or “Edmundson wheels.”
Comparing helical wheel representations for helical segments and non-helical segments made it clear that residues with hydrophobic side chains occur significantly more often in helical regions. One the other hand, the non-helical regions have more polar side chains.
Moreover, helical wheels helped researchers understand how helices might interact. Schiffer and Edmundson found that the residues “inside” myoglobin were hydrophobic. By lining up the helical wheels with their hydrophobic residues pointing to the center of the protein molecule, they were able to visualize inter-helical interactions. “So, even without a three-dimensional structure to look at, one could think about a molecule,” writes Schiffer.
Extrapolating from known structures like myoglobin, hemoglobin, and lysozyme, Schiffer and Edmundson deduced three-dimensional features of six proteins for which only the sequences were known. One of these was insulin, for which the calculated helical content of 39% approximately agreed with published values of 38–59% as obtained by optical rotatory dispersion.(2) Dr. Schiffer also predicted helical content for cytochrome c, ribonuclease A, chymotrypsinogen A, TMV protein, and human growth hormone.
Biophysical Journal received this article for publication in September 1966 and it was published the following year in March. After the submission of this work, Prothero (1966) proposed a statistical method to predict the distribution of alpha helices from amino acid sequences, which was also published in the Biophysical Journal.(3) However, he did not provide any insight into the physical significance of the helical segments.
Dr. Schiffer concludes that “helical wheels became as useful in studying the structure and interactions of proteins as we had hoped it would.” Today these diagrams can be regularly drawn using computer programs such as helixvis and HeliQuest.
[1] Schiffer, Marianne, and Allen B. Edmundson. Use of helical wheels to represent the structures of proteins and to identify segments with helical potential. Biophys J. 1967. 7:121–135.
[2] Urnes, Peter, and Paul Doty. Optical rotation and the conformation of polypeptides and proteins. Advances in protein chemistry. 1962. Academic Press. Vol. 16: 401–544.
[3] Prothero, J. W. Correlation between the distribution of amino acids and alpha helices. Biophys J. 19666:367–370.
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