Protein Structure Prediction and Design in a Biologically Realistic Implicit Membrane
Protein Structure Prediction and Design in a Biologically Realistic Implicit Membrane
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DOI：
10.1016/j.bpj.2020.03.006
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发表时间：
2020-04-21
影响因子：
3.4
通讯作者：
Gray, Jeffrey J.
中科院分区：
文献类型：
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作者：
Alford, Rebecca F.;Fleming, Patrick J.;Gray, Jeffrey J.
蛋白质设计是阐明功能机制和设计新疗法和纳米技术的有力工具。虽然可溶性蛋白质的设计已经取得了进展，膜蛋白质的设计仍然具有挑战性，因为在建模的脂质双层的困难。在这项工作中，我们开发了一种隐式方法，该方法可以捕获具有不同脂质组成的膜的各向异性结构，水填充孔的形状和纳米尺度。该模型提高了计算基准对实验目标的性能，包括预测蛋白质在双层中的取向，DDG计算，天然结构的歧视，和天然序列恢复。当应用于从头蛋白质设计时，这种方法设计的序列的氨基酸分布接近膜蛋白中的天然氨基酸分布，克服了以前的膜模型中容易产生富含亮氨酸的设计的关键缺陷。此外，在新的膜模型中设计的蛋白质表现出天然的功能，包括界面芳香族侧链，疏水长度与双层厚度兼容，和极性孔。我们的方法推进了高分辨率的膜蛋白结构预测和设计，以解决关键的生物学问题和工程挑战。
Protein design is a powerful tool for elucidating mechanisms of function and engineering new therapeutics and nanotechnologies. Although soluble protein design has advanced, membrane protein design remains challenging because of difficulties in modeling the lipid bilayer. In this work, we developed an implicit approach that captures the anisotropic structure, shape of water-filled pores, and nanoscale dimensions of membranes with different lipid compositions. The model improves performance in computational benchmarks against experimental targets, including prediction of protein orientations in the bilayer, DDG calculations, native structure discrimination, and native sequence recovery. When applied to de novo protein design, this approach designs sequences with an amino acid distribution near the native amino acid distribution in membrane proteins, overcoming a critical flaw in previous membrane models that were prone to generating leucine-rich designs. Furthermore, the proteins designed in the new membrane model exhibit native-like features including interfacial aromatic side chains, hydrophobic lengths compatible with bilayer thickness, and polar pores. Our method advances high-resolution membrane protein structure prediction and design toward tackling key biological questions and engineering challenges.