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Peptide-induced disruption of lipid membranes is central to both amyloid diseases and the activity of antimicrobial peptides. Here, we combine all-atom molecular dynamics simulations with biophysical experiments to investigate how four amphipathic peptides interact with lipid bilayers. All peptides adsorb on the membrane surface. Peptide M01 [Ac-(FKFE)2-NH2] self-assembles into β-sheet nanofibrils that span both leaflets of the membrane, creating water-permeable channels. The other three peptides adopt α-helical structures at the water–lipid interface. Peptide M02 [Ac-FFKKFFEE-NH2], a sequence isomer of M01, does not form β-sheet aggregates and is too short to span the bilayer, resulting in no observable water permeation across the membrane. Peptides M03 and M04 are α-helical isomers long enough to span the bilayer, with a polar face that allows the penetration of water deep inside the membrane. For the M03 peptide [Ac-(FFKKFFEE)2-NH2], insertion into the bilayer starts with the nonpolar N-terminal amino acids penetrating the hydrophobic core of the bilayer, while electrostatic interactions hold negative residues at the C-terminus on the membrane surface. The M04 peptide, [Ac-FFKKFFEEFKKFFEEF-NH2], is made by relocating a single nonpolar residue from the central region of M03 to the C-terminus. This nonpolar residue becomes unfavorably exposed to the solvent upon insertion of the N-terminal region of the peptide into the membrane. Consequently, higher concentrations of M04 peptides are required to induce water permeation compared to M03. Overall, our comparative analysis reveals how subtle rearrangements of polar and nonpolar residues modulate peptide-induced water permeation. This provides mechanistic insights relevant to amyloid pathology and antimicrobial peptide design.
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An Alternative Mechanistic Paradigm for the Electrochemical C‐Terminal Decarboxylation of Peptides
The C‐terminal decarboxylation of peptides provides an important opportunity to synthesize modern peptide pharmaceuticals that contain C‐terminal amides. This transformation can be achieved by electrochemical oxidation; however, the standard implementation depends on oxidation potential for selectivity which may represent a challenge when amino acid residues containing electroactive side chains are present. To address this limitation, an alternative mechanistic paradigm has been introduced for selective decarboxylation of a C‐terminal carboxylate, one that relies on a chelation event. In a proof‐of‐principle experiment used to probe and define the viability of this mechanism, it is demonstrated that the combination of an iron mediator and a C‐terminal glutamate residue can be used to conduct the reaction in the presence of the more electron‐rich tyrosine residue frequently found in medicinally active peptides. Investigations into the reaction specifics and the scope/limitations provide key insights into the reaction mechanism and how such processes can be optimized. The success of the method highlighted here points to a more general binding‐based approach to drive C‐terminal decarboxylation that utilizes a functional group motif not possible at any other position in a peptide.
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- Award ID(s):
- 2002158
- PAR ID:
- 10642365
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemElectroChem
- Volume:
- 12
- Issue:
- 14
- ISSN:
- 2196-0216
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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