Fernández Ariel, Shen Min-yi, Colubri Andrés, Sosnick Tobin R, Berry R Stephen, Freed Karl F
Institute for Biophysical Dynamics, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, USA.
Biochemistry. 2003 Jan 28;42(3):664-71. doi: 10.1021/bi026510i.
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.
绒毛蛋白头部片段在体外能自主折叠，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。根据AGADIR标准，即使是N端螺旋也不太有利。我们的粗粒度从头算模拟揭示了三体相关性，其中疏水残基定位以保护酰胺-羰基氢键免受水的攻击，从而诱导C端螺旋的生长并指导折叠过程。在使用隐式溶剂模型的全原子模拟中也发现了类似的相关性，该模型能准确再现使用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环境，可通过引入某些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的非明显残基的突变来进行实验探究。
