Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Uppal Road, Hyderabad 500 007, INDIA.
J Biomol Struct Dyn. 2010 Feb;27(4):541-50. doi: 10.1080/07391102.2010.10507337.
Mammalian defensins are crucial components of the innate immune system. They are characterized by three disulfide bridges and exhibit broad spectrum antibacterial activity. The spacing between the cysteines and disulfide connectivities in the two classes of defensins, the alpha- and beta-forms, are different. The structural motif of 3 beta-strands appears to be conserved in alpha- and beta-defensins despite differences in disulfide connectivities and spacing between cysteines. In this study, Molecular Dynamics Simulations (MDS) have been carried out to study the conformational behavior of alpha- andbeta-defensins with and without disulfide bridges. Our results indicate that beta-strands in the C-terminal region of HBD-1 and HNP-3 do not unfold during the course of MDS. The segment adopting alpha-helix in HBD-1 unfolds early during the simulations. The backbone hydrogen bonds in HBD-1 and HNP-3 are broken during MDS. When the disulfide bonds are absent, the N-terminal beta- strand unfolds by 20 ns but beta-strands are observed in the C-terminal region of HNP-3. HBD-1, without disulfide bridges, unfolds to a greater extent during the course of the MDS. Examination of distances between sulfur atoms of cysteines without disulfide bridges during the simulations indicate that there is no specific preference for native disulfide bridges, which could be the reason for the experimental observation of non-native disulfide bridge formation during chemical synthesis of human alpha- and beta-defensins. Since defensins with non-native disulfide bridges are biologically active, the exact three dimensional structures observed for native HBD-1 and HNP-3 does not appear to be essential for exhibiting antibacterial activity.
哺乳动物防御素是先天免疫系统的重要组成部分。它们的特征是有三个二硫键，并具有广谱的抗菌活性。在 α-和β-防御素这两类防御素中，半胱氨酸之间的间隔和二硫键的连接方式不同。尽管在二硫键的连接方式和半胱氨酸之间的间隔上存在差异，但 3 β-链的结构模体似乎在 α-和β-防御素中都得到了保守。在这项研究中，进行了分子动力学模拟（MDS），以研究有和没有二硫键的 α-和β-防御素的构象行为。我们的结果表明，HBD-1 和 HNP-3 的 C 末端区域的 β-链在 MDS 过程中不会展开。HBD-1 中采用 α-螺旋的片段在模拟早期展开。HBD-1 和 HNP-3 的骨架氢键在 MDS 过程中被打破。当二硫键不存在时，N 端的 β-链在 20 ns 内展开，但在 HNP-3 的 C 末端区域仍观察到 β-链。没有二硫键的 HBD-1 在 MDS 过程中展开的程度更大。在模拟过程中检查没有二硫键的半胱氨酸的硫原子之间的距离表明，没有对天然二硫键的特定偏好，这可能是在化学合成人类 α-和 β-防御素时观察到非天然二硫键形成的实验观察结果的原因。由于具有非天然二硫键的防御素具有生物活性，因此观察到的天然 HBD-1 和 HNP-3 的精确三维结构似乎对于表现出抗菌活性并不是必需的。
