Through the insertion of nonpolar side chains into the bilayer, the hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how the changing chemical composition of the bilayer affects the magnitude side chain transfer free energies (ΔG°sc) has historically not been well understood. A particularly challenging region for experimental interrogation is the bilayer interfacial region that is characterized by a steep polarity gradient. In this study we have determined the ΔG°sc for nonpolar side chains as a function of bilayer position using a combination of experiment and simulation. We discovered an empirical correlation between the surface area of nonpolar side chain, the transfer free energies, and local water concentration in the membrane that allows for ΔG°sc to be accurately estimated at any location in the bilayer. Using these water-to-bilayer ΔG°sc values, we have calculated the interface-to-bilayer transfer free energy (ΔG°(i,b)). We find that the ΔG°(i,b) are similar to the biological, translocon-based transfer free energies, indicating that the translocon energetically mimics the bilayer interface. Together these findings can be applied to increase the accuracy of computational workflows used to identify and design membrane proteins, as well bring greater insight into our understanding of how disease-causing mutations affect membrane protein folding and function.

中文翻译：

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局部双层疏水性调节膜蛋白的稳定性

通过将非极性侧链插入双层中，疏水作用早已被接受为膜蛋白折叠的驱动力。然而，历史上尚不清楚双分子层的化学组成的变化如何影响侧链转移自由能（ΔG°sc）的大小。用于实验询问的特别具有挑战性的区域是双层界面区域，其特征在于陡峭的极性梯度。在这项研究中，我们结合实验和模拟确定了非极性侧链的ΔG°sc与双层位置的关系。我们发现了非极性侧链的表面积与转移自由能之间的经验相关性，膜中的局部水浓度可以在双层中的任何位置准确估算ΔG°sc。使用这些水到双层的ΔG°sc值，我们计算了界面到双层的转移自由能（ΔG°（i，b））。我们发现ΔG°（i，b）类似于生物学的，基于Translocon的转移自由能，表明Translocon能量上模仿了双层界面。这些发现共同可以提高识别和设计膜蛋白的计算流程的准确性，并为我们对引起疾病的突变如何影响膜蛋白折叠和功能的理解提供更深刻的了解。b）类似于生物，基于转运子的转移自由能，表明转运子在能量上模仿了双层界面。这些发现共同可以提高识别和设计膜蛋白的计算流程的准确性，并为我们对引起疾病的突变如何影响膜蛋白折叠和功能的理解提供更深刻的了解。b）类似于生物的，基于转运子的转移自由能，表明转运子在能量上模仿了双层界面。这些发现共同可以提高识别和设计膜蛋白的计算流程的准确性，并为我们对引起疾病的突变如何影响膜蛋白折叠和功能的理解提供更深刻的了解。