Abstract
BP100 is a short antimicrobial peptide and can also act as a molecule-carrier into cells. Like with other antimicrobial peptides, the precise mechanism of membrane disruption is not fully understood. Here we use computer simulations to understand, at a molecular level, the initial interaction between BP100 and zwitterionic/negatively charged model membranes. In agreement with experimental results, our simulations showed BP100 folded into an alpha helix when in contact with negatively charged membranes. BP100 binding induced the aggregation of negatively charged lipids on mixed membranes composed of zwitterionic and anionic lipids. The peptide in alpha-helix conformation initially interacts with the membrane via electrostatic interactions between the negatively charged lipids and the positively charged residues of the peptide. At that point the peptide flips, burying the hydrophobic residues into the bilayer highlighting the importance of the hydrophobic effect contribution to the initial interaction of cationic antimicrobial peptides with membranes.
Highlights
Cationic antimicrobial peptides (CAMPs) are short-length, amphiphilic, rich in basic residues of the innate immune system of complex organisms, serving as the first defense line against pathogens
In a study with Brownian Dynamics simulations with a coarse-grained peptide model, Alves et al.[18] simulated BP100 confined in model membranes at 293 K for 1 μs each and reported the high stability of BP100 pre-folded alpha helix and a threefold decrease in its lateral diffusion in POPC: POPG membranes relative to that in POPC membrane[18]
Circular Dichroism (CD) shows that BP100 is random in solution[10,11,30], and our simulations reproduced these data
Summary
Cationic antimicrobial peptides (CAMPs) are short-length, amphiphilic, rich in basic residues of the innate immune system of complex organisms, serving as the first defense line against pathogens. CAMPs can potentially give rise to a new generation of drugs due to their broad spectrum of antimicrobial activity against bacteria, rare cases of the appearance of AMP-resistant bacteria, selectivity, and rapid effects. MD simulations were utilized to study BP100’s structure and activity: Wang Y. et al.[17] performed an 8 μs-long MD simulation of BP100 in DMPC bilayer and found that BP100 remained in the surface-bound-state inserting through its C-terminus. They reported the unfolding of BP100 N-terminus (Lys[1] and Lys2) after 1.5.
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