Large-scale context in protein folding:: Villin headpiece
Large-scale context in protein folding:: Villin headpiece
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DOI：
10.1021/bi026510i
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发表时间：
2003-01-28
期刊：
影响因子：
2.9
通讯作者：
Freed, KF
中科院分区：
文献类型：
--
作者：
Fernández, A;Shen, MY;Freed, KF
绒毛头部在体外自主折叠，形成三个α-螺旋区域。然而，局部倾向强烈不利于C-末端螺旋的形成，因为该螺旋中的大多数天然残基对是疏水/极性错配的。甚至N-末端螺旋也是不利的，根据AGA 1标准。我们的粗粒度从头计算模拟揭示了三体相关性，其中疏水残基的位置，以保护酰胺-羰基氢键免受水的攻击，从而诱导C-末端螺旋的生长和指导折叠过程。类似的相关性也被发现在全原子模拟与隐式溶剂模型，准确地再现与显式溶剂分子的模拟结果。这些相关性建立了一个大规模的多体背景，可以通过引入某些非明显残基的突变来实验探测，这些残基位于天然疏水核心之外，但预计会显著影响折叠速率和动力学。
The villin headpiece folds autonomously in vitro forming three alpha-helical regions. Local propensities, however, strongly disfavor the formation of the C-terminal helix because most native residue pairs in that helix are hydrophobic/polar mismatches. Even the N-terminal helix is unfavored according to the AGADIR criterion. Our coarse-grained ab initio simulations reveal three-body correlations in which hydrophobic residues position to protect amide-carbonyl hydrogen bonds from attack by water, thus inducing the growth of the C-terminal helix and guiding the folding process. Similar correlations are also found in all-atom simulations with an implicit solvent model that accurately reproduces the results of simulations with explicit solvent molecules. The correlations establish a large-scale, many-body context that may be probed experimentally by introducing mutations of certain nonobvious residues that reside outside the native hydrophobic core but that are predicted to affect the folding rates and dynamics dramatically.