Baldwin Quenisha, Sumpter Bobby, Panagiotou Eleni
Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA.
Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.
Polymers (Basel). 2022 Jul 26;14(15):3014. doi: 10.3390/polym14153014.
The novel coronavirus SARS-CoV-2 infects human cells using a mechanism that involves binding and structural rearrangement of its Spike protein. Understanding protein rearrangement and identifying specific amino acids where mutations affect protein rearrangement has attracted much attention for drug development. In this manuscript, we use a mathematical method to characterize the local topology/geometry of the SARS-CoV-2 Spike protein backbone. Our results show that local conformational changes in the FP, HR1, and CH domains are associated with global conformational changes in the RBD domain. The SARS-CoV-2 variants analyzed in this manuscript (alpha, beta, gamma, delta Mink, G614, N501) show differences in the local conformations of the FP, HR1, and CH domains as well. Finally, most mutations of concern are either in or in the vicinity of high local topological free energy conformations, suggesting that high local topological free energy conformations could be targets for mutations with significant impact of protein function. Namely, the residues 484, 570, 614, 796, and 969, which are present in variants of concern and are targeted as important in protein function, are predicted as such from our model.
新型冠状病毒SARS-CoV-2利用一种涉及其刺突蛋白结合和结构重排的机制感染人类细胞。了解蛋白质重排并确定突变影响蛋白质重排的特定氨基酸，在药物开发方面引起了广泛关注。在本论文中，我们使用一种数学方法来表征SARS-CoV-2刺突蛋白主链的局部拓扑结构/几何形状。我们的结果表明，FP、HR1和CH结构域的局部构象变化与RBD结构域的整体构象变化相关。本论文中分析的SARS-CoV-2变体（α、β、γ、δ貂、G614、N501）在FP、HR1和CH结构域的局部构象上也存在差异。最后，大多数关注的突变位于局部拓扑自由能高的构象内部或附近，这表明局部拓扑自由能高的构象可能是对蛋白质功能有重大影响的突变靶点。也就是说，我们的模型预测，在关注的变体中存在且被认为对蛋白质功能重要的484、570、614、796和969位残基就是这样。
