Effect of helical kink in antimicrobial peptides on membrane pore formation

Abstract

Every cell is protected by a semipermeable membrane. Peptides with the right properties, for example Antimicrobial peptides (AMPs), can disrupt this protective barrier by formation of leaky pores. Unfortunately, matching peptide properties with their ability to selectively form pores in bacterial membranes remains elusive. In particular, the proline/glycine kink in helical peptides was reported to both increase and decrease antimicrobial activity. We used computer simulations and fluorescence experiments to show that a kink in helices affects the formation of membrane pores by stabilizing toroidal pores but disrupting barrel-stave pores. The position of the proline/glycine kink in the sequence further controls the specific structure of toroidal pore. Moreover, we demonstrate that two helical peptides can form a kink-like connection with similar behavior as one long helical peptide with a kink. The provided molecular-level insight can be utilized for design and modification of pore-forming antibacterial peptides or toxins.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…For example, studies of pardaxin in the membrane have demonstrated the importance of cationic residues and phenylalanine residues on peptide association with lipids [806]. Finally, MD simulations allow for the study of the effect of chemical modification on the peptides (e.g., amidation) [787] and the effect of helical kink on peptide insertion into the bilayer [816,817].…”

Modification Strategy of D-leucine Residue Addition on a Novel Peptide from Odorrana schmackeri, with Enhanced Bioactivity and In Vivo Efficacy

“…Homology analysis and functional prediction used the BLAST programme and UniProt database, which showed that this peptide belonged to the brevinin-1 family, which has multiple potential functions. Like other brevinin-1 peptides ( Figure 1 B), in addition to having the distinctive feature of a rana box, B1OS had the highly conserved residues of Ala9, which tended to contribute to helix formation [ 19 ], and Pro14, which induced a stable kink facilitating toroidal pore formation in bacterial membranes [ 20 ]. Interestingly, by alignment comparison, it was found that an FLP motif at the N-terminus was highly conserved in most brevinin-1 family members, whereas a hydrophobic leucine residue was lacking at the second position of B1OS and brevinin-1HSb.…”

Novel Antimicrobial Peptides from a Cecropin-Like Region of Heteroscorpine-1 from Heterometrus laoticus Venom with Membrane Disruption Activity

“…The glycine-proline hinge region was added to the mutant peptides, considering that almost all cecropin and cecropin-like peptides contain the alanine glycine-proline region [ 31 ]. The glycine-proline hinge region in the middle of the helical structure can benefit the pore-forming peptides [ 40 ]. Conversely, another study about cecropin attempting to delete the proline-glycine hinge resulted in decreasing antimicrobial activity, although there was an increase in anti-inflammatory activity [ 41 ].…”

“…The result was in line with the estimate that most helicity improvements usually increase the activity of peptides [ 46 ]. It was suspected that the addition of the glycine-proline hinge region increased the overall helicity value of the peptides [ 40 ]. Despite, the insertion of proline might be interrupted the helical span [ 47 ], the deletion of negative charge residues helped to conform an idealized amphipathic helix, with distinct hydrophobic and hydrophilic facets [ 22 ].…”