Awang Tadsanee, Pongprayoon Prapasiri
Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand.
Computational Biomodelling Laboratory for Agricultural Science and Technology (CBLAST), Kasetsart University, Bangkok, 10900, Thailand.
J Mol Model. 2018 Sep 5;24(10):273. doi: 10.1007/s00894-018-3812-7.
Human α-defensin 5 (HD5) is one of the important antimicrobial peptides (AMPs) used against a broad-spectrum of pathogens, especially Gram-negative bacteria. HD5 kills by disrupting and making a pore in the bacterial membrane. The presence of lipopolysaccharide (LPS), located on a membrane surface, is found to have an impact on HD5's activity, where such binding mechanism in microscopic detail remains unclear. In this work, we therefore employed molecular dynamics (MD) simulations to investigate the binding mechanisms of HD5 on LPS in comparison to a bare DMPC lipid membrane. Two oligomers, dimer and tetramer, are studied here. Apparently, the membrane structure influences the protein binding affinity. HD5 binds tighter to a lipid membrane than LPS. Both dimeric and tetrameric HD5 can penetrate deeply into a phosphate layer in a lipid membrane, whereas only facial contacts are observed for LPS systems. The proteins appear to stay in the polar area instead of diving into a hydrophobic region. Furthermore, it happens in all cases that residues in the active region (A1, T2, R6, R13, R32) contribute to the membrane adsorption. The breakdown of tetramer into two dimers is also found. This implies that the dimer is more favorable for membrane binding. Moreover, both dimeric and tetrameric HD5 can significantly disrupt a LPS layer, whilst no serious distortion of lipid membrane is obtained. This emphasizes the importance of LPS on HD5 activity.
人α-防御素5（HD5）是一种重要的抗菌肽（AMP），可对抗多种病原体，尤其是革兰氏阴性菌。HD5通过破坏细菌膜并在其上形成孔来杀死细菌。位于膜表面的脂多糖（LPS）的存在被发现会影响HD5的活性，但其微观层面的结合机制仍不清楚。因此，在这项工作中，我们采用分子动力学（MD）模拟来研究HD5与LPS的结合机制，并与裸露的二肉豆蔻酰磷脂酰胆碱（DMPC）脂质膜进行比较。这里研究了两种寡聚体，即二聚体和四聚体。显然，膜结构会影响蛋白质的结合亲和力。HD5与脂质膜的结合比与LPS的结合更紧密。二聚体和四聚体形式的HD5都能深入脂质膜的磷酸层，而LPS体系仅观察到表面接触。蛋白质似乎停留在极性区域，而不是深入疏水区域。此外，在所有情况下，活性区域（A1、T2、R6、R13、R32）中的残基都有助于膜吸附。还发现四聚体分解为两个二聚体。这意味着二聚体更有利于膜结合。此外，二聚体和四聚体形式的HD5都能显著破坏LPS层，而脂质膜没有严重变形。这强调了LPS对HD5活性的重要性。
