Solution Structure of a Bent α-Helix^†,‡

We present the solution structure determination of a peptide with sequence Ac-WEAQAREALAKEAQARA-NH₂, using NMR data. The peptide has a high population of a stable α-helical structure in the middle with fraying ends. In addition, our data are consistent with the presence of several other transient and interconverting conformers. The peptide sequence was designed using amino acids that have propensity for α-helix specificity. The presence of E−R/K (i, i + 4) ion pairs was expected to enhance the stability of the α-helix by introducing favorable electrostatic interactions at the side chain level, in addition to the characteristic backbone (i, i + 4) hydrogen bonds. The NMR structural ensemble demonstrates competition between E−R/K (i, i + 4) and (i, i − 1) ion pair formation, with the (i, i − 1) interactions being dominant. The relative topologies of the charged side chains demonstrate flexibility and overall compromised favorable medium/long-range electrostatic interactions. The peptide α-helix is bent despite the lack of an amphipathic sequence. Bending is introduced by a strong (i, i + 8) hydrophobic interaction between the side chains of N-terminal tryptophan and leucine at the middle of the peptide sequence.

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