Pathways of hLL-37_17-29 Aggregation Give Insight into the Mechanism of α-Amyloid Formation

Abstract

α-amyloids present a novel self-assembly principle that can be utilized to prepare functional biomaterials. Evidence of αamyloid formation in the active core of the human LL-37 protein (comprising residues 17 to 29) was associated with this peptide's membranolytic property. Though mechanistic pathways of β-amyloid formation are known, such studies are scarce in α-amyloids. Modern computational techniques allow such mechanistic studies in molecular detail. Here, we propose aggregation pathways in hLL-37 17-29 through molecular dynamics simulations. We first identified oligomers among peptides based on a distance criterion. The distribution of oligomers was then used to build Markov state models from which pathways were obtained using the framework of transition path theory. We checked the structural stability of the peptides during oligomerization, which is crucial from their functional point of view. We also investigated the key residues that participate in oligomer formation, the interactions between them, and the effect of residue mutations on the binding free energy of the peptides. Our findings suggest that larger oligomers are produced from the association of smaller and intermediate oligomers. The peptides retain their helical structure during aggregation with transient occurrences of 3-10 helix and turns. Hydrophobic interactions are vital in the aggregation of these peptides with Ile24 playing a crucial role. Mutation of this residue to alanine decreases the peptides' binding free energy, resulting in reduced aggregation tendency.

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

“…In addition to the structure of the LL-37 monomer, the structures of the oligomers of LL-37 are important to better understand the stability of the peptide against enzymatic degradation. LL-37 has been shown to form aggregates at high peptide concentrations in solution [ 212 , 213 , 214 , 215 ]. Sancho-Vaello et al also explored the structure of LL-37 dimers in a detergent-free environment (5NNM), as well as in DPC (5NNT) and LDAO (5NNK) micelles [ 208 ].…”