The alphabet of intrinsic disorder: II. Various roles of glutamic acid in ordered and intrinsically disordered proteins

Uversky, Vladimir N

Glutamic acid in α-helix caps. Since α-helices in peptides and proteins have an overall dipole moments caused by the cumulative effects of all the individual dipoles from the carbonyl groups of the peptide bond pointing along the helix axis, the overall helical structure is destabilized due to the noticeable entropic effects. The effect of this helical dipole moment can be approximated by placing 0.5-0.7 positive unit charge near the N-terminus and 0.5-0.7 negative unit charge near the C-terminus of the helix. 67, 68 One of the Nature's strategies to neutralize this helix dipole is the specific capping of the N-terminal ends of α-helices by negatively charged residues, such as glutamic acids. 67, 68 Furthermore, careful analysis of α-helices revealed that their first and last four residues differ from the remaining residues by being unable to make intrα-helical hydrogen bonds. Instead, these first four (> N-H) groups and last four (> C = O) groups in an α-helix are often capped by alternative hydrogen bond partners. [69] [70] [71] Physico-chemical and statistical analysis suggested that certain residues are more preferable at the C-and N-termini of an α-helix (the helical C-and N-caps). 70 For example, based on the analysis of series of mutations in the two N-caps of barnase, it was concluded that a single N-cap can stabilize the protein by up to ~2.5 kcal/mol. 70 Importantly, the presence of a negative charge of the N-cap was shown to add ~1.6 kcal/mol of stabilization energy mostly due to the compensation effects for the macroscopic electrostatic dipole of the helix. 70 From a global survey among proteins of known structure, seven distinct capping motifs are identified-three at the helix N-terminus and four at the C-terminus. 71 One of these motifs is the helix-capping motif Ser-X-X-Glu, a sequence that occurs frequently at the N-termini of α-helices in proteins. [71] [72] [73] Thermodynamic analysis of this Ser-X-X-Glu motif from the ramachandran plots for backbone conformations of the 18 non-glycine and non-proline amino acids. Marked regions of density correspond to the right-handed α-helix region (α), mirror image of α (α L ), region largely involved in β-sheet formation (β S ), and region associated with extended polyproline-like helices, but also observed in β-sheet (β P ).