Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human β-defensin analog
Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human β-defensin analog
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DOI：
10.1038/s42003-019-0653-6
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发表时间：
2019-11-01
影响因子：
5.9
通讯作者：
Wang, Tuo
中科院分区：
文献类型：
--
作者：
Kang, Xue;Elson, Christopher;Wang, Tuo
人β -防御素（hBD）在对抗各种微生物的抗菌活性和免疫调节中发挥核心作用。这些肽扰乱磷脂膜的功能，但在分子水平上，防御素是如何接近、插入并最终破坏磷脂膜的还不是很清楚。本研究表明，hBD-3类似物通过溶液结构中两个相邻环形成的保守表面与脂质双分子层相互作用。通过将C-13， H-1和P-31固态核磁共振方法与长期分子动力学模拟相结合，我们发现膜结合使肽固化，增强结构多态性，并促进β -链构象。肽与带负电荷的脂质共定位，限制头群运动，使膜变形成更小的椭球状囊泡。本研究确定了hBD-3类似物的残基特异性、膜结合拓扑结构，为进一步阐明其他防御素的功能相关结构和动力学奠定了基础，并促进了模拟防御素抗生素、抗真菌药和抗炎药的开发。
Human beta-defensins (hBD) play central roles in antimicrobial activities against various microorganisms and in immune-regulation. These peptides perturb phospholipid membranes for function, but it is not well understood how defensins approach, insert and finally disrupt membranes on the molecular level. Here we show that hBD-3 analogs interact with lipid bilayers through a conserved surface that is formed by two adjacent loops in the solution structure. By integrating a collection of C-13, H-1 and P-31 solid-state NMR methods with long-term molecular dynamic simulations, we reveal that membrane-binding rigidifies the peptide, enhances structural polymorphism, and promotes beta-strand conformation. The peptide colocalizes with negatively charged lipids, confines the headgroup motion, and deforms membrane into smaller, ellipsoidal vesicles. This study designates the residue-specific, membrane-bound topology of hBD-3 analogs, serves as the basis for further elucidating the function-relevant structure and dynamics of other defensins, and facilitates the development of defensin-mimetic antibiotics, antifungals, and anti-inflammatories.