An Amino Acid Packing Code for α-Helical Structure and Protein Design

This work demonstrates that all packing in alpha-helices can be simplified to repetitive patterns of a single motif: the knob-socket. Using the precision of Voronoi Polyhedra/Delauney Tessellations to identify contacts, the knob-socket is a four-residue tetrahedral motif: a knob residue on one alpha-helix packs into the three-residue socket on another alpha-helix. The principle of the knob-socket model relates the packing between levels of protein structure: the intra-helical packing arrangements within secondary structure that permit inter-helix tertiary packing interactions. Within an alpha-helix, the three-residue sockets arrange residues into a uniform packing lattice. Inter-helix packing results from a definable pattern of interdigitated knob-socket motifs between two alpha-helices. Furthermore, the knob-socket model classifies three types of sockets: (1) free, favoring only intra-helical packing; (2) filled, favoring inter-helical interactions; and (3) non, disfavoring alpha-helical structure. The amino acid propensities in these three socket classes essentially represent an amino acid code for structure in alpha-helical packing. Using this code, we used a novel yet straightforward approach for the design of alpha-helical structure to validate the knob-socket model. Unique sequences for three peptides were created to produce a predicted amount of alpha-helical structure: mostly helical, some helical, and no helix. These three peptides were synthesized, and helical content was assessed using CD spectroscopy. The measured alpha-helicity of each peptide was consistent with the expected predictions. These results and analysis demonstrate that the knob-socket motif functions as the basic unit of packing and presents an intuitive tool to decipher the rules governing packing in protein structure. (C) 2012 Elsevier Ltd. All rights reserved.