Aromatic Amino Acids Promote Peptide Folding by Reducing Backbone Hydration

Abstract

The relation between the sequence of a protein and its tridimensional structure remains largely unknown. To better understand how single residues impact on the local protein structure, we studied peptides of sequence EGAAXAASS (X = Gly, Ile, Tyr, Trp) through comparison of molecular dynamics (MD) trajectories and NMR residual dipolar coupling (RDC) measurements. The RDC patterns of the peptide with X = Gly or Ile are rather flat, suggesting extended, unfolded peptides, while the contrasted patterns for peptides with X = Tyr or Trp suggest compact folded structures. The comparison shows that the formation of internal hydrogen bonds underlying helical-turns is key to reproduce experimental RDC values for the peptides containing aromatic residues. The simulations further reveal that the driving force leading to such helical-turn conformation arises from the lack of hydration of the peptide chain on either side of the bulky aromatic side chain, which can potentially act as a nucleation point initiating the folding process. These results provide a starting point to understand the amino acid code underlying the mechanism of protein folding.