Abstract

Truncated host-defense peptide derived from chicken angiogenin 4 (mChAng-4, c-(CRFKFRIVIC)) is a membrane active peptide displaying antibacterial properties. The structural properties of mChAng-4 are related to its function and aggregation properties. The cyclic nature of mChAng-4 makes its structure more constrained and stable compared to its linear analog. We study the structure and dynamics of single mChAng-4 peptides in solution as well as multi-chain mChAng-4 systems comprising eight peptides to investigate their aggregation. To investigate the effect of hydrophobicity on the structure, we study the native mChAng-4 (c-(CRFKFRIVIC)) and a valine substituted analog (c-(CRFKFRVVVC)). We compare the L and D configurations of the peptides as D-peptides are known to be more stable in a biological context due to a lack of D-specific peptidases. We compare the inverted sequence in L and D form (c-(CIVIRFKFRC)) to address differences between L and D enantiomers. An alanine scan revealed which residues were essential toward folding. We increase the rigidity of the peptide by replacing the disulfide linkage with an amide bridge. The analysis of the 500 μs ensemble of single peptide simulations shows that single peptides in solution display varying degrees of β sheet formation. Oligomerization was investigated in a 36 μs ensemble of the native, double valine mutant, linear, Dab, Dap, and native systems. The analysis of the 36 μs ensemble of aggregation systems suggested the linear, Dab, and Dap were more likely to aggregate in solution, but further analysis is needed to draw conclusions about the oligomerization states.