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The penetration of human defensin 5 (HD5) through bacterial outer membrane: simulation studies

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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.

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Abbreviations

MD:

Molecular dynamics

SMD:

Steered molecular dynamics

LPS:

Lipopolysaccharide

HD5:

Human α-defensin 5

LINC:

Linear constraint solver

KDO:

3-Deoxy-d-manno-octulosonic acid

REMP:

Re-LPS

PVP:

Palmitoyl vaccenyl phosphatidyl

VMD:

Visual molecular dynamics

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Funding

We would like to thank Kasetsart University Research and Development Institute (KURDI, grant no. FF(KU) 25.64), Faculty of Science, Department of Chemistry (BRF policy), and Science Achievement Scholarship of Thailand (SAST) for financial support.

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TA conducted the simulations, analyzed data, and wrote a manuscript. PP analyzed data and wrote a manuscript.

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Correspondence to Prapasiri Pongprayoon.

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Awang, T., Pongprayoon, P. The penetration of human defensin 5 (HD5) through bacterial outer membrane: simulation studies. J Mol Model 27, 291 (2021). https://doi.org/10.1007/s00894-021-04915-w

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