Correlation of three-dimensional structures with the antibacterial activity of a group of peptides designed based on a nontoxic bacterial membrane anchor
Correlation of three-dimensional structures with the antibacterial activity of a group of peptides designed based on a nontoxic bacterial membrane anchor
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DOI：
10.1074/jbc.m410116200
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发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Li, X
中科院分区：
文献类型：
--
作者：
Wang, GS;Li, YF;Li, X
为了了解对应于大肠杆菌酶IIA（Glc）的N-末端序列的无毒膜锚和类似序列的毒性抗菌肽aurein 1.2之间的功能差异，设计了一系列肽来桥接它们之间的差距。改变膜锚上的一个残基就可以将其转化为抗菌肽。圆二色谱表明，所有的肽在水中是无序的，但在胶束中的螺旋。通过溶液NMR光谱法在膜模拟胶束中测定肽的结构。基于距离的结构的质量通过包括衍生自来自天然丰度二维异质结相关光谱的一组化学位移（H-1（α）、N-15、C-13（α）和C-13（β））的主链角度约束而得到改善。与膜锚不同，抗菌肽具有更宽和更长的疏水表面，允许更深地渗透到膜中，如肽和短链二辛酰磷脂酰甘油之间的分子间核Overhauser效应交叉峰所支持的。尝试将这些肽的NMR结构与其抗菌活性相关联。这组肽的活性与螺旋性、两亲性、电荷、电荷数、疏水表面的大小或疏水转移自由能不完全相关。然而，在肽活性和膜扰动电位之间建立了相关性，在阳离子肽的情况下，膜扰动电位由界面疏水补丁和碱性残基定义。事实上，脂质双层的P-31固态NMR光谱表明，这些肽对脂质囊泡的破坏程度与其膜扰动电位成比例。
To understand the functional differences between a nontoxic membrane anchor corresponding to the N-terminal sequence of the Escherichia coli enzyme IIA(Glc) and a toxic antimicrobial peptide aurein 1.2 of similar sequence, a series of peptides was designed to bridge the gap between them. An alteration of a single residue of the membrane anchor converted it into an antibacterial peptide. Circular dichroism spectra indicate that all peptides are disordered in water but helical in micelles. Structures of the peptides were determined in membrane-mimetic micelles by solution NMR spectroscopy. The quality of the distance-based structures was improved by including backbone angle restraints derived from a set of chemical shifts (H-1(alpha), N-15, C-13(alpha) and C-13(beta)) from natural abundance two-dimensional heteronuclear correlated spectroscopy. Different from the membrane anchor, antibacterial peptides possess a broader and longer hydrophobic surface, allowing a deeper penetration into the membrane, as supported by intermolecular nuclear Overhauser effect cross-peaks between the peptide and short chain dioctanoyl phosphatidylglycerol. An attempt was made to correlate the NMR structures of these peptides with their antibacterial activity. The activity of this group of peptides does not correlate exactly with helicity, amphipathicity, charge, the number of charges, the size of the hydrophobic surface, or hydrophobic transfer free energy. However, a correlation is established between the peptide activity and membrane perturbation potential, which is defined by interfacial hydrophobic patches and basic residues in the case of cationic peptides. Indeed, P-31 solid state NMR spectroscopy of lipid bilayers showed that the extent of lipid vesicle disruption by these peptides is proportional to their membrane perturbation potential.