Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan 48824, USA.
J Phys Chem B. 2010 Dec 9;114(48):15969-75. doi: 10.1021/jp104746g. Epub 2010 Nov 15.
There is increasing evidence that a polypeptide chain in solvent conditions that favor folding may have transient structure and is significantly more compact than a fully denatured chain. However, there is no sequence-dependent model to capture such interactions. In this work, we present a simple and computationally inexpensive model based on a wormlike chain with excluded volume. The probability distribution of millions of such chains is reweighted to bias compact conformations in which residues of similar hydrophobicity are located near each other. This model, which has one adjustable parameter, is fit to measured values of intramolecular contact formation, which has been shown to be extremely sensitive to various models of intrachain distances. We show that under various denaturant concentrations, there is good convergence of the model for several different sequences with a wide range of dynamics. We also show that this model quantitatively predicts paramagnetic resonance enhancement (PRE) measurements with no adjustable parameters. Therefore a simple, probabilistic model that accounts for sequence-specific interactions may give a more realistic starting point for predictions of protein folding.
越来越多的证据表明，在有利于折叠的溶剂条件下，多肽链可能具有瞬态结构，并且比完全变性的链显著更紧凑。然而，目前还没有基于序列的模型可以捕捉到这种相互作用。在这项工作中，我们提出了一个简单且计算成本低廉的模型，该模型基于具有排除体积的线状链。对数百万条这样的链的概率分布进行了重新加权，以偏向于紧凑构象，其中具有相似疏水性的残基彼此靠近。该模型有一个可调参数，可拟合测量到的分子内接触形成值，该值已被证明对各种链内距离模型非常敏感。我们表明，在不同的变性剂浓度下，对于具有广泛动力学范围的几个不同序列，该模型具有良好的收敛性。我们还表明，该模型可以定量预测无可调参数的顺磁磁共振增强 (PRE) 测量值。因此，一种简单的、基于概率的模型，该模型可以解释序列特异性相互作用，可能为蛋白质折叠的预测提供更现实的起点。
