Department of Physics, Institute of Biosciences, Letters and Exact Sciences, São Paulo State University, São José do Rio Preto 15054-000, Brazil.
Laboratório de Biofísica Teórica, Departamento de Física, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, Uberaba 38064-200, Brazil.
J Phys Chem B. 2021 Oct 28;125(42):11673-11686. doi: 10.1021/acs.jpcb.1c07663. Epub 2021 Oct 13.
Molecular crowding is a ubiquitous phenomenon in biological systems, with significant consequences on protein folding and stability. Small compounds, such as the osmolyte trimethylamine -oxide (TMAO), can also present similar effects. To analyze the effects arising from these solute-like molecules, we performed a series of crowded coarse-grained folding simulations. Two well-known proteins were chosen, CI2 and SH3, modeled by the alpha-carbon-structure-based model. In the simulations, the crowding molecules were represented by low-sized neutral atom beads in different concentrations. The results show that a low level of the volume fraction occupied by neutral agents can change protein stability and folding kinetics for the two systems. However, the kinetics were shown to be unaffected in their respective folding temperatures. The faster kinetics correlates with changes in the folding route for systems at the same temperature, where non-native contacts were shown to be relevant. The transition states of the two systems with and without crowders are similar. In the case of SH3, there are differences in the structuring of two strands, which may be associated with the increase in its folding rate, in addition to the destabilization of the denatured ensemble. The present study also detected a crossover in the thermodynamic stability behavior, previously observed experimentally and theoretically. As the temperature increases, crowders change from destabilizing to stabilizing agents.
分子拥挤是生物系统中普遍存在的现象，对蛋白质折叠和稳定性有重要影响。小分子，如渗透剂三甲胺氧化物（TMAO），也可能产生类似的影响。为了分析这些类似溶质分子产生的影响，我们进行了一系列拥挤的粗粒折叠模拟。选择了两个著名的蛋白质，CI2 和 SH3，通过基于α-碳原子结构的模型进行建模。在模拟中，用不同浓度的低尺寸中性原子珠来代表拥挤分子。结果表明，低水平的中性试剂占据的体积分数可以改变两种体系的蛋白质稳定性和折叠动力学。然而，在各自的折叠温度下，动力学不受影响。较快的动力学与相同温度下系统折叠途径的变化相关，其中非天然接触被证明是相关的。有和没有拥挤剂的两个系统的过渡态相似。在 SH3 的情况下，两条链的结构存在差异，这可能与折叠速率的增加有关，除了变性集合的去稳定化之外。本研究还检测到了先前在实验和理论上观察到的热力学稳定性行为的交叉。随着温度的升高，拥挤剂从去稳定化试剂变为稳定化试剂。
