Pressure Unfolding of Proteins: New Insights into the Role of Bound Water
Pressure Unfolding of Proteins: New Insights into the Role of Bound Water
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DOI：
10.1021/acs.jpcb.1c04398
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发表时间：
2021-07-26
影响因子：
3.3
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Arsiccio, Andrea;Shea, Joan-Emma
高压可能对蛋白质稳定性有害，导致解折叠和功能丧失。这种现象的发生是因为展开转变伴随着体积的减小，这通常归因于由于填充缺陷而存在于天然状态中的空腔的消除。我们提出了一种新的计算方法，使研究压力展开的原子详细的蛋白质模型在隐式溶剂。我们包括压力的影响，使用的转移自由能项，使我们能够解耦的蛋白质残基和结合水分子展开后的体积变化的影响。我们讨论了分子动力学模拟结果，使用该协议的两个模型蛋白质，色氨酸笼和葡萄球菌核酸酶（SNase）。我们发现，结合水的体积减少是关键的能量项，驱动蛋白质变性的影响下的压力，色氨酸笼和SNase。然而，我们注意到较小的Trp笼和较大的SNase蛋白之间的展开机制的差异。事实上，SNase而不是Trp笼的解折叠被认为进一步伴随着内腔体积的减少。我们的研究结果表明，对于小肽，如色氨酸笼，压力变性是由溶剂可及性的增加，在展开后，和随后的结合水分子的数量增加。对于较大的蛋白质，如SNase，天然折叠内的空腔作为弱点，决定了对压力变性的整体抗性。我们的模拟显示出惊人的协议与SNase实验获得的压力展开的配置文件，并代表了一个有前途的方法，计算效率高，准确的压力诱导的蛋白质变性的探索。
High pressures can be detrimental for protein stability, resulting in unfolding and loss of function. This phenomenon occurs because the unfolding transition is accompanied by a decrease in volume, which is typically attributed to the elimination of cavities that are present within the native state as a result of packing defects. We present a novel computational approach that enables the study of pressure unfolding in atomistically detailed protein models in implicit solvent. We include the effect of pressure using a transfer free energy term that allows us to decouple the effect of protein residues and bound water molecules on the volume change upon unfolding. We discuss molecular dynamics simulations results using this protocol for two model proteins, Trp-cage and staphylococcal nuclease (SNase). We find that the volume reduction of bound water is the key energetic term that drives protein denaturation under the effect of pressure, for both Trp-cage and SNase. However, we note differences in unfolding mechanisms between the smaller Trp-cage and the larger SNase protein. Indeed, the unfolding of SNase, but not Trp-cage, is seen to be further accompanied by a reduction in the volume of internal cavities. Our results indicate that, for small peptides, like Trp-cage, pressure denaturation is driven by the increase in solvent accessibility upon unfolding, and the subsequent increase in the number of bound water molecules. For larger proteins, like SNase, the cavities within the native fold act as weak spots, determining the overall resistance to pressure denaturation. Our simulations display a striking agreement with the pressure-unfolding profile experimentally obtained for SNase and represent a promising approach for a computationally efficient and accurate exploration of pressure-induced denaturation of proteins.