The role of primary sequence in helical control compared across short α- and β³-peptides

Abstract

α-helices are the most common form of secondary structure found in proteins. In order to study controlled protein folding, as well as manipulate the interface of helical peptides with targets in protein–protein interactions, many techniques have been developed to induce and stabilize α-helical structure in short synthetic peptides. Furthermore, short, non-natural β-peptides have been established that fold into predictable 14-helices that mimic α-helical structure. We created a panel of short 6–8 residue α- and β-peptides that used confirmed primary sequence design features which influence helical control and directly compared the helicity across peptides with the most minimal epitopes. Using CD spectroscopy, we found that both α- and β-peptides abided by their respective design principles, with no significant “cross-helicity” inducing an α- or a β-peptide to fold into the oppositely controlled helix. Generally, the β-peptide of the most optimal sequence displayed the largest percent of 14-helicity, whereas the two α-peptides of most favorable design showed some α-helicity and a marked 3₁₀-helical contribution. Overall, the results can inform future peptidomimetic designs, especially in the development of short, structured peptides with biological function.

Keywords:

• helices
• peptides
• primary sequence
• β-peptides
• circular dichroism
• peptide synthesis

Acknowledgments

We thank The College of New Jersey for start-up funding and continued laboratory support. We thank Dr Michelle Bunagan for help and training with the instrumentation. Also, we thank the students from the Spring 2013 CHE470 Advanced Topics in Chemical Biology class at TCNJ: Ms Kristen DeMeester, Mr John Farrokh, Mr Ari Goldwaser, Ms Jessica Gruskos, Mr Tyler Higgins, Ms Emily Leonard, Mr Kevin Nelson, Mr Devon Pesce, Ms Bhavini Prajapati, Mr Dhaval Shah, Mr Gregory Tilley, and Mr Stefan Turan for unpublished early work on the synthesis and CD spectroscopy of these peptides in a different buffer.