Dipartimento di Fisica, Università di Roma Tor Vergata and Sezione di Roma Tor Vergata, INFN, Via della Ricerca Scientifica 1, I-00133 Roma, Italy.
Istituto di Chimica dei Composti Organometallici, Consiglio Nazionale delle Ricerche, Via Madonna del Piano 10, I-50019 Firenze, Italy.
Molecules. 2022 Mar 17;27(6):1955. doi: 10.3390/molecules27061955.
Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich's ataxia) and several types of cancer. By using altruistic metadynamics in conjunction with the maximal constrained entropy principle, we estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants. The sampled configurations highlight differences between the wild-type and mutated sequences in the stability of the folded state. In partial agreement with thermodynamic experiments, where most of the analyzed variants are characterized by lower thermal stability compared to wild type, the D104G variant is found with a stability comparable to the wild-type sequence and a lower water-accessible surface area. These observations, obtained with the new approach we propose in our work, point to a functional switch, affected by single-point mutations, of frataxin from iron storage to iron release. The method is suitable to investigate wide structural changes in proteins in general, after a proper tuning of the chosen collective variable used to perform the transition.
铁蛋白 (FXN) 是一种参与线粒体中铁储存和运输的蛋白质。 基因中的单点突变导致功能性铁蛋白的产量降低，从而导致铁的动态平衡失调。 FXN 变体是神经损伤（弗里德里希共济失调）和几种类型癌症的基础。 通过使用利他主义的元动力学结合最大约束熵原理，我们估计铁蛋白展开和一些病理突变体的自由能变化。 采样的构象突出了野生型和突变序列在折叠状态稳定性方面的差异。 在部分同意热力学实验的情况下，其中大多数分析的变体与野生型相比具有较低的热稳定性，发现 D104G 变体的稳定性与野生型序列相当，并且水可及表面积较低。 这些观察结果是通过我们在工作中提出的新方法获得的，表明铁蛋白从铁储存到铁释放的功能转换受到单点突变的影响。 该方法适用于一般蛋白质的广泛结构变化，前提是对用于进行转换的所选集体变量进行适当调整。
