The a-helix-stabilizing effect of different amino acid residues at the helical termini of short peptides in aqueous solution has been determined. Several dodecapeptides containing alanine, asparagine, aspartate, glutamine, glutamate, and serine at the amino terminus and arginine, lysine, and alanine at the carboxyl terminus were synthesized, and the a-helical content of each peptide was measured by using circular dichroism spectroscopy. The trend in a-helix-inducing ability of these amino acids was found to be as follows: In an a-helix, NH donors of the first four residues and CO acceptors of the last four residues lack intrahelical hydrogenbond partners. Presta and Rose (19) hypothesized that a necessary condition for helix formation is the presence of residues flanking the helix termini that have side chains to supply hydrogen-bond partners for unpaired main-chain NH and CO groups. Richardson and Richardson (20), by surveying several proteins of known structures, showed that at the amino termini of helices, there is a preponderance of amino acids with side chains that could hydrogen-bond with the free NH groups of the helix. Gierasch and coworkers (21) have shown that side-chain-backbone hydrogen bonding, as proposed by Presta and Rose, may also stabilize helix formation in peptides. Site-directed mutagenesis studies involving the amino-terminal residues of a-helices in native proteins have shown the significance of such hydrogen bonding in protein stability (22,23).We decided to test the Presta and Rose hypothesis in a peptide designed to fold into an isolated a-helix (24). The rationale for the design is as follows. (i) We chose a short a-helical segment (12 residues) resembling most a-helices found in native proteins. Further, we expected the capping effects to be more prominent in a short peptide. (ii) We introduced a proline and a glycine, amino acids traditionally known to be helix breakers, at positions 2 and 11, respectively, to demarcate the helical ends (25). We also hoped that the presence of the helix breakers might enable the side chains of the end residues to turn around and hydrogen-bond with the free NH and CO groups at the helical termini. (iii) The presence of a glutamate at position 4 and a lysine at position 7 increases solubility of the peptide and may also stabilize the helix by salt bridge formation (14). (iv) The rest of the amino acids were chosen to be alanine, which has a high tendency to form a-helices (26). (v) The respective positively and negatively charged side chains of arginine at the carboxyl end and aspartate at the amino end are expected to interact favorably with the helical dipole and stabilize the a-helix (13). (vi) The negatively charged carboxyl group of Arg-12 is amidated to eliminate repulsive interactions -between itself and the negative pole of the helical dipole. (vii) The a amino group of residue 1 was not acylated to prevent such an amide carbonyl from hydrogen bonding with the free NH groups at the amino terminus. The sequences of our model peptide an...
The occurrence of beta-sheet motifs in a number of neurodegenerative disorders has brought about the need for the de novo design of soluble model beta-sheet complexes. Such model complexes are expected to further the understanding of the interconversion processes that occur from cellular allowed random coil or alpha-helical conformation into insoluble cell-deleterious beta-pleated-sheet motifs. In the present study, polyalanine-based peptides (i.e., derived from Ac-KA14K-NH2) were designed that underwent conformational changes from monomeric random coil conformations into soluble, macromolecular beta-pleated-sheet complexes without any covalent modification. The interconversion was found to be length-, environment-, and concentration-dependent and to be driven by hydrophobic interactions between the methyl groups of the alanine side chains. A series of substitution analogs of Ac-KA14K-NH2 was used to study the amino acid acceptability within the hydrophobic core of the complex, as well as at both termini. The formation of amyloid plaques in a number of amyloidogenic peptides could be related to the presence of amino acids within their sequences that were found to have a high propensity to occur in these model beta-sheet complexes.
The conformational propensity of the 20 naturally occurring amino acids was determined in aqueous 3‐[N‐morpholino]propane‐sulfonic acid (MOPS) buffer, protein interior‐like [nonmicellar sodium dodecylsulfate (SDS)] and membrane‐like environments (micellar SDS and lysophosphatidylglycerol/lysophosphatidylcholine micelles) using a single “guest” position in a polyalanine‐based model host peptide (Ac‐KYA13K‐NH2). This model system allows the intrinsic α‐helical or β‐sheet propensity of the amino acids to be determined without intra‐ and interchain side chain interactions. The overall environment dependence observed for the conformational propensity for the amino acids studied confirms the importance of determining propensity in lipidic environments to better elucidate the biological functions of proteins. The hydrophobic interactions between peptide side chains and lipids appeared to be the primary forces driving the conformational induction in lipidic environments of the model peptides studied. Finally, when comparing the results of these studies with those reported in the literature, the local environment was found to highly influence 65% of the 20 naturally occurring amino acids. © 1997 John Wiley & Sons, Inc. Biopoly 42: 489–498, 1997
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