Jang Hyunbum, Ma Buyong, Nussinov Ruth
Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
BMC Struct Biol. 2007 Apr 2;7:21. doi: 10.1186/1472-6807-7-21.
Protegrin-1 (PG-1) is known as a potent antibiotic peptide; it prevents infection via an attack on the membrane surface of invading microorganisms. In the membrane, the peptide forms a pore/channel through oligomerization of multiple subunits. Recent experimental and computational studies have increasingly unraveled the molecular-level mechanisms underlying the interactions of the PG-1 beta-sheet motifs with the membrane. The PG-1 dimer is important for the formation of oligomers, ordered aggregates, and for membrane damaging effects. Yet, experimentally, different dimeric behavior has been observed depending on the environment: antiparallel in the micelle environment, and parallel in the POPC bilayer. The experimental structure of the PG-1 dimer is currently unavailable.
Although the beta-sheet structures of the PG-1 dimer are less stable in the bulk water environment, the dimer interface is retained by two intermolecular hydrogen bonds. The formation of the dimer in the water environment implies that the pathway of the dimer invasion into the membrane can originate from the bulk region. In the initial contact with the membrane, both the antiparallel and parallel beta-sheet conformations of the PG-1 dimer are well preserved at the amphipathic interface of the lipid bilayer. These beta-sheet structures illustrate the conformations of PG-1 dimer in the early stage of the membrane attack. Here we observed that the activity of PG-1 beta-sheets on the bilayer surface is strongly correlated with the dimer conformation. Our long-term goal is to provide a detailed mechanism of the membrane-disrupting effects by PG-1 beta-sheets which are able to attack the membrane and eventually assemble into the ordered aggregates.
In order to understand the dimeric effects leading to membrane damage, extensive molecular dynamics (MD) simulations were performed for the beta-sheets of the PG-1 dimer in explicit water, salt, and lipid bilayers composed of POPC lipids. Here, we studied PG-1 dimers when organized into a beta-sheet motif with antiparallel and parallel beta-sheet arrangements in an NCCN packing mode. We focus on the conformations of PG-1 dimers in the lipid bilayer, and on the correlation between the conformations and the membrane disruption effects by PG-1 dimers. We investigate equilibrium structures of the PG-1 dimers in different environments in the early stage of the dimer invasion. The dimer interface of the antiparallel beta-sheets is more stable than the parallel beta-sheets, similar to the experimental observation in micelle environments. However, we only observe membrane disruption effects by the parallel beta-sheets of the PG-1 dimer. This indicates that the parallel beta-sheets interact with the lipids with the beta-sheet plane lying obliquely to the bilayer surface, increasing the surface pressure in the initial insertion into the lipid bilayer. Recent experimental observation verified that parallel PG-1 dimer is biologically more active to insert into the POPC lipid bilayer.
防御素-1（PG-1）是一种强效抗菌肽；它通过攻击入侵微生物的膜表面来预防感染。在膜中，该肽通过多个亚基的寡聚化形成孔道/通道。最近的实验和计算研究越来越多地揭示了PG-1β-折叠基序与膜相互作用的分子水平机制。PG-1二聚体对于寡聚体、有序聚集体的形成以及膜损伤效应很重要。然而，在实验中，根据环境观察到了不同的二聚体行为：在胶束环境中为反平行，在POPC双层中为平行。目前尚无PG-1二聚体的实验结构。
尽管PG-1二聚体的β-折叠结构在本体水环境中不太稳定，但二聚体界面通过两个分子间氢键得以保留。在水环境中形成二聚体意味着二聚体侵入膜的途径可能起源于本体区域。在与膜的初始接触中，PG-1二聚体的反平行和平行β-折叠构象在脂质双层的两亲界面处都得到了很好的保留。这些β-折叠结构说明了PG-1二聚体在膜攻击早期的构象。在这里我们观察到PG-1β-折叠在双层表面的活性与二聚体构象密切相关。我们的长期目标是提供PG-1β-折叠破坏膜的详细机制，其能够攻击膜并最终组装成有序聚集体。
为了理解导致膜损伤的二聚体效应，我们对PG-1二聚体的β-折叠在由POPC脂质组成的明确水、盐和脂质双层中进行了广泛的分子动力学（MD）模拟。在这里，我们研究了以NCCN堆积模式组织成具有反平行和平行β-折叠排列的β-折叠基序的PG-1二聚体。我们关注PG-1二聚体在脂质双层中的构象，以及构象与PG-1二聚体膜破坏效应之间的相关性。我们研究了二聚体侵入早期不同环境中PG-1二聚体的平衡结构。反平行β-折叠的二聚体界面比平行β-折叠更稳定，这与在胶束环境中的实验观察结果相似。然而，我们仅观察到PG-1二聚体的平行β-折叠具有膜破坏效应。这表明平行β-折叠与脂质相互作用时，β-折叠平面倾斜于双层表面，在最初插入脂质双层时增加了表面压力。最近的实验观察证实，平行PG-1二聚体在生物学上更具活性，能够插入POPC脂质双层。
