片段分子轨道计算表明，E200K 突变显著改变了人类朊病毒蛋白的局部结构稳定性。
Fragment molecular orbital calculations reveal that the E200K mutation markedly alters local structural stability in the human prion protein.
机构信息
AdvanceSoft Corporation, Akasaka, Tokyo, Japan.
出版信息
Prion. 2010 Jan-Mar;4(1):38-44. doi: 10.4161/pri.4.1.10890. Epub 2010 Jan 4.
Abstract
The E200K mutation of the human prion protein (PrP) is known to cause familial Creutzfeldt-Jakob disease. In order to elucidate the effects of the mutation on the local structural stability of PrP, we performed ab initio fragment molecular orbital calculations for the wild-type human PrP and the E200K variant modeled under neutral and mild acidic conditions. The calculations revealed that this substitution markedly altered the intramolecular interactions in the PrP, suggesting that the local structural instabilities induced by the E200K mutation might cause initial denaturation of the PrP and its subsequent conversion to a pathogenic form. This work presents a new approach for quantitatively elucidating structural instabilities in proteins that cause misfolding diseases.
摘要
人类朊病毒蛋白（PrP）的 E200K 突变已知会导致家族性克雅氏病。为了阐明该突变对 PrP 局部结构稳定性的影响，我们在中性和轻度酸性条件下对野生型人类 PrP 和 E200K 突变体进行了从头分子轨道碎片计算。计算结果表明，这种取代显著改变了 PrP 中的分子内相互作用，表明 E200K 突变引起的局部结构不稳定性可能导致 PrP 的初始变性及其随后转化为致病形式。这项工作为定量阐明导致错误折叠疾病的蛋白质的结构不稳定性提供了一种新方法。
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