马朊蛋白结构稳定性的分子动力学研究
The Structural Stability of Wild-type Horse Prion Protein - Molecular Dynamics Studies
摘要：
朊病毒疾病{ \it（例如Creutzfeldt-Jakob病（CJD）、变异型CJD（vCJD）、Gerstmann-Str $\ddot{\text{a}}$ ussler-Scheinker综合征（GSS）、人的致死性家族性传染病（FFI）和库鲁病、羊的瘙痒病、牛海绵状脑病（BSE或“疯牛病”）和牛的慢性消耗性疾病（CWD）}总是影响人类和动物的致死性和高度传染性神经变性疾病。然而，到目前为止，还没有一些有效的治疗方法或药物来治疗所有这些朊病毒疾病。据报道，兔、狗和马是唯一能抵抗从其他物种分离的朊病毒疾病感染的哺乳动物物种。最近，已报道$β$ 2- $α$ 2环有助于它们的蛋白质结构稳定性。作者发现，兔子朊病毒蛋白有一个很强的盐桥ASP 177-ARG 163（就像一个拉紧的弓弦）保持这个环连接。本文证实，这种盐桥也有助于马朊蛋白的结构稳定性。因此，$β$ 2- $α$ 2环区域可能是潜在的药物靶点区域。除了这一重要的盐桥外，另外四个重要的盐桥GLU 196-ARG 156-HIS 187、ARG 156-ASP 202和GLU 211-HIS 177也对马朊蛋白的结构稳定性有很大贡献。马朊蛋白的盐桥、氢键和疏水接触等方面的数据丰富。
英文摘要：
Prion diseases {\it (e.g. Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), Gerstmann-Str$\ddot{\text{a}}$ussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE or `mad-cow' disease) and chronic wasting disease (CWD) in cattles)} are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. However, by now there have not been some effective therapeutic approaches or medications to treat all these prion diseases. Rabbits, dogs, and horses are the only mammalian species reported to be resistant to infection from prion diseases isolated from other species. Recently, the $β$2-$α$2 loop has been reported to contribute to their protein structural stabilities. The author has found that rabbit prion protein has a strong salt bridge ASP177-ARG163 (like a taut bow string) keeping this loop linked. This paper confirms that this salt bridge also contributes to the structural stability of horse prion protein. Thus, the region of $β$2-$α$2 loop might be a potential drug target region. Besides this very important salt bridge, other four important salt bridges GLU196-ARG156-HIS187, ARG156-ASP202 and GLU211-HIS177 are also found to greatly contribute to the structural stability of horse prion protein. Rich databases of salt bridges, hydrogen bonds and hydrophobic contacts for horse prion protein can be found in this paper.
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