Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States.
CHDI Management/CHDI Foundation , Los Angeles, California 90045, United States.
J Am Chem Soc. 2017 Jul 5;139(26):8820-8827. doi: 10.1021/jacs.7b00838. Epub 2017 Jun 23.
There exists strong correlation between the extended polyglutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntington's disease (HD); however, the underlying molecular mechanism is still poorly understood. Here we apply extensive molecular dynamics simulations to study the folding of Htt-exon-1 across five different polyQ-lengths. We find an increase in secondary structure motifs at longer Q-lengths, including β-sheet content that seems to contribute to the formation of increasingly compact structures. More strikingly, these longer Q-lengths adopt supercompact structures as evidenced by a surprisingly small power-law scaling exponent (0.22) between the radius-of-gyration and Q-length that is substantially below expected values for compact globule structures (∼0.33) and unstructured proteins (∼0.50). Hydrogen bond analyses further revealed that the supercompact behavior of polyQ is mainly due to the "glue-like" behavior of glutamine's side chains with significantly more side chain-side chain H-bonds than regular proteins in the Protein Data Bank (PDB). The orientation of the glutamine side chains also tend to be "buried" inside, explaining why polyQ domains are insoluble on their own.
亨廷顿病（HD）的发病年龄与亨廷顿蛋白（Htt）第 1 外显子中延伸的多聚谷氨酰胺（polyQ）之间存在很强的相关性；然而，其潜在的分子机制仍知之甚少。在这里，我们应用广泛的分子动力学模拟来研究 Htt-exon-1 在五种不同的 polyQ 长度下的折叠情况。我们发现，随着 Q 长度的增加，二级结构模体增加，包括β-折叠含量似乎有助于形成越来越紧凑的结构。更引人注目的是，这些更长的 Q 长度采用了超紧凑的结构，这可以从旋转半径和 Q 长度之间的惊人小幂律标度指数（0.22）得到证明，该指数大大低于紧凑球状体结构（约 0.33）和无结构蛋白质（约 0.50）的预期值。氢键分析进一步表明，polyQ 的超紧凑行为主要是由于谷氨酰胺侧链的“胶状”行为，其侧链-侧链氢键比蛋白质数据库（PDB）中的常规蛋白质多得多。谷氨酰胺侧链的取向也往往“埋藏”在内部，这解释了为什么 polyQ 结构域本身不溶解。
