Abstract
Human α-defensin 5 (HD5) is one of cationic antimicrobial peptides which plays a crucial role in an innate immune system in human body. HD5 shows the killing activity against a broad spectrum of pathogenic bacteria by making a pore in a bacterial membrane and penetrating into a cytosol. Nonetheless, its pore-forming mechanisms remain unclear. Thus, in this work, the constant-velocity steered molecular dynamics (SMD) simulation was used to simulate the permeation of a dimeric HD5 into a gram-negative lipopolysaccharide (LPS) membrane model. Arginine-rich HD5 is found to strongly interact with a LPS surface. Upon arrival, arginines on HD5 interact with lipid A head groups (a top part of LPS) and then drag these charged moieties down into a hydrophobic core resulting in the formation of water-filled pore. Although all arginines are found to interact with a membrane, Arg13 and Arg32 appear to play a dominant role in the HD5 adsorption on a gram-negative membrane. Furthermore, one chain of a dimeric HD5 is required for HD5 adhesion. The interactions of arginine-lipid A head groups play a major role in adhering a cationic HD5 on a membrane surface and retarding a HD5 passage in the meantime.
Highlights
Antimicrobial peptides (AMPs) are a class of small peptides that are important for the innate immune system in organisms
These two applied forces refer to the barriers for dragging Human α-defensin 5 (HD5) out of a hydrophobic core (F3) and phospholipid head groups (F4)
The electrostatic interactions between HD5 and lipid A head groups cause a charged LPS surface to be a facilitator for the HD5 adhesion, but hindrance for the passage of HD5 at the same time
Summary
Antimicrobial peptides (AMPs) are a class of small peptides that are important for the innate immune system in organisms. AMPs have a wide range of antimicrobial activities against bacteria, fungi, viruses, and parasites [1, 2]. All defensins share two common features which are a cationic region (the so-called “active region”) and hydrophobic patch. Both α- and β-defensins have three disulfide bonds (Cys1—Cys, Cys2—Cys, Cys3— Cys in α-defensins and Cys1—Cys, Cys2—Cys, Cys3—Cys in β-defensins) and three-stranded β-sheet structures (β1- β3 in Fig. 1A), whereas θ-defensins form cyclic structures [4]. HNP1—HNP4 are found in neutrophil granules, whereas HD5 and HD6 are expressed in Paneth cells [6]
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