Molecular Transfer Model for pH Effects on Intrinsically Disordered Proteins: Theory and Applications
Molecular Transfer Model for pH Effects on Intrinsically Disordered Proteins: Theory and Applications
复制标题
pH 对本质无序蛋白质影响的分子转移模型：理论与应用
DOI：
10.1021/acs.jctc.0c01316
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发表时间：
2021
影响因子：
5.5
通讯作者：
Thirumalai, D.
中科院分区：
文献类型：
--
作者：
Mugnai, Mauro Lorenzo;Thirumalai, D.
我们提出了一种理论方法来研究 pH 值的变化如何塑造本质无序蛋白质 (IDP) 探索的异质构象整体。该理论是在粗粒度模型的背景下发展起来的，可以在给定的质子化状态下快速、准确和广泛地探索构象空间。为了考虑 pH 效应，我们推广了分子转移模型 (MTM)，其中使用转移自由能重新加权构象，这是在新环境中使系统的“冻结”构象达到平衡所需的自由能。使用半宏系综，我们得出了转移自由能的精确表达式，这相当于所有质子化态的适当总和。由于精确结果的计算要求太高，无法用于大型聚电解质或 IDP，因此我们引入了转移自由能的平均场 (MF) 近似。使用晶格模型，我们比较了转移自由能的精确结果和 MF 结果以及与模型 IDP 相关的各种可观测值。我们发现带电基团（序列）的精确位置，而不仅仅是净电荷，决定了结构特性。我们证明，当研究无序聚合物时，先前提到的 MF 理论在球状蛋白背景下的一些局限性得到了缓解。精确结果与 MF 结果之间的良好一致性使我们能够使用此处介绍的方法作为计算工具来研究 IDP 和其他生物系统的特性随 pH 的变化。
We present a theoretical method to study how changes in pH shape the heterogeneous conformational ensemble explored by intrinsically disordered proteins (IDPs). The theory is developed in the context of coarse-grained models, which enable a fast, accurate, and extensive exploration of conformational space at a given protonation state. In order to account for pH effects, we generalize the molecular transfer model (MTM), in which conformations are re-weighted using the transfer free energy, which is the free energy necessary for bringing to equilibrium in a new environment a “frozen” conformation of the system. Using the semi-grand ensemble, we derive an exact expression of the transfer free energy, which amounts to the appropriate summation over all the protonation states. Because the exact result is computationally too demanding to be useful for large polyelectrolytes or IDPs, we introduce a mean-field (MF) approximation of the transfer free energy. Using a lattice model, we compare the exact and MF results for the transfer free energy and a variety of observables associated with the model IDP. We find that the precise location of the charged groups (the sequence), and not merely the net charge, determines the structural properties. We demonstrate that some of the limitations previously noted for MF theory in the context of globular proteins are mitigated when disordered polymers are studied. The excellent agreement between the exact and MF results poises us to use the method presented here as a computational tool to study the properties of IDPs and other biological systems as a function of pH.