Structural stability of wild type and mutated α-keratin fragments:: Molecular dynamics and free energy calculations
Structural stability of wild type and mutated α-keratin fragments:: Molecular dynamics and free energy calculations
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DOI：
10.1021/bm049788u
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发表时间：
2004-11-01
影响因子：
6.2
通讯作者：
Wortmann, FJ
中科院分区：
文献类型：
--
作者：
Danciulescu, C;Nick, B;Wortmann, FJ
本研究的目的是研究点突变对卷曲螺旋片段的结构稳定性的人发中间丝分子动力学模拟和自由能计算的影响。人类头发角蛋白基因hHb6的螺旋终止基序的突变似乎与遗传性毛发营养不良Monilethrix有关。最常见的突变是Glu413Lys和Glu413Asp，位于IF卷曲螺旋2B杆状结构域的C末端。根据我们的模拟，显着的构象变化的侧链在突变和邻近的网站发生由于Glu413Lys突变。此外，热力学积分法计算的Glu 413向Lys转化过程中，静电相互作用的差异导致了自由能的较大变化.据推测，适应突变的卷曲螺旋中的相互作用所必需的结构重排导致IF组装或其稳定性的变化。第二个突变，Glu413Asp，仅导致计算的自由能差的一个小值，该值在模拟的误差范围内。因此，必须得出结论，该突变不影响卷曲螺旋稳定性。
The objective of this study is to investigate the influence of point mutations on the structural stability of coiled coil fragments of the human hair intermediate filament by molecular dynamics simulations and free energy calculations. Mutations in the helix termination motif of human hair keratin gene hHb6 seem to be connected to the hereditary hair dystrophy Monilethrix. The most common mutations reported are Glu413Lys and Glu413Asp, located at the C-terminal end of the coiled coil 2B rod domain of the IF. According to our simulations, significant conformational changes of the side chains at the mutation and neighboring sites occur due to the Glu413Lys mutation. Furthermore, the differences in electrostatic interactions cause a large chan-e in free energy during transformation of Glu413 to Lys calculated by the thermodynamic integration approach. It is speculated that the structural rearrangement necessary to adapt the interactions in the mutated coiled coil leads to changes in the IF assembly or its stability. The second mutation, Glu413Asp, only leads to a small value of the calculated free energy difference that is within the error limits of the simulations. Thus, it has to be concluded that this mutation does not affect the coiled coil stability.