Background: Familial Mediterranean Fever (FMF) is a prototypical hereditary autoinflammatory disease affecting principally Mediterranean populations and characterized by recurrent frequent fever and inflammation. The disease is essentially caused by inherited mutations in the MEFV gene which encodes pyrin protein. The reported mutations are mostly located on the B30.2 domain in the C-terminal end of the protein.

Objective: The present study reports a structural comparison of the five most common mutated structures including M694V, V726A, M694I, R761H, and M680I. The aim of this study was to determine the structural and functional disorders caused by the mutations in the human pyrin protein.

Results: The comparison revealed that all mutations make overall changes in the structure of the domain. Further, the effects of these mutations on structural and molecular behavior of the B30.2 domain were compared with the native structure using MD simulation by GROMACS software. The results revealed that all the studied mutants have a destabilizing effect on the protein structure. Additionally, analyzing the projection of the motions of the proteins in phase space demonstrates high rigidity of the mutated structures in comparison with the native protein.

Conclusion: The results of simulations elucidate how the mutations affect the physiological functioning of the pyrin B30.2 domain and cause the occurrence of the FMF disease.

中文翻译：

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突变人Pyrin B30.2结构域的结构和功能分析

背景：家族性地中海热（FMF）是一种典型的遗传性自发性疾病，主要影响地中海人口，其特征是经常反复发烧和发炎。该疾病基本上是由编码吡喃蛋白的MEFV基因中的遗传突变引起的。报告的突变大多位于蛋白质C末端的B30.2结构域上。

目的：本研究报告了五个最常见的突变结构（包括M694V，V726A，M694I，R761H和M680I）的结构比较。这项研究的目的是确定由人类吡啶蛋白突变引起的结构和功能障碍。

结果：比较结果表明，所有突变均使结构域发生整体变化。此外，使用GROMACS软件通过MD模拟，将这些突变对B30.2结构域的结构和分子行为的影响与天然结构进行了比较。结果表明，所有研究的突变体均对蛋白质结构具有去稳定作用。另外，分析蛋白质在相空间中的运动的投影表明，与天然蛋白质相比，突变结构具有很高的刚性。

结论：仿真结果阐明了突变如何影响吡喃B30.2结构域的生理功能并导致FMF疾病的发生。