Small peptides are generally considered conformationally dynamic. However, classical models of protein folding predict that they should indeed adopt native states. Recent work from our laboratory examined this notion in the context of small neuropeptides, and this talk describes our work moving to a longer family of peptide sequences. The neuropeptide galanin has a thirty-five-year history as an intriguing target in drug design, owing to its implication as a potential anticonvulsant and neuronal trophic factor among many other therapeutically interesting functions including analgesia and mood alteration. However, despite years of medicinal chemistry study and some biophysical characterization, there are still no high-resolution descriptions of the intrinsic three-dimensional structure of galanin. We present the NMR structural characterization of several fragments of the galanin N-terminus in buffered aqueous solution. This analysis utilizes modified hydrogen-bonding and dihedral angle restraints to reflect chemical shift patterns in the data suggestive of a weakly-folded helix - a long-standing hypothesis regarding the conformation of this functionally critical portion of the galanin sequence. The presented structures depict a core of hydrophobic residues that cluster together regardless of the presence of helical structure, and correspond to residues in the N-terminus of galanin that have been previously shown to be critical for binding its receptors. The fact that multiple peptide backbone arrangements can accommodate a nearly identical sidechain display raises interesting questions regarding the relationship between a given peptide’s sequence patterning and its ability to present a functional and, often, selective protein-binding epitope.

Minimal increments of hydrophobic collapse within the N-terminus of the neuropeptide galanin

ACS Spring Meeting 2021

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