Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout,Molecular Omics

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Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout
Molecular Omics ( IF 3.0 ) Pub Date : 2020-10-28 , DOI: 10.1039/d0mo00103a
Peng Zhou _{1,

2,

3,

4,

5} , Heyi Wang _{1,

2,

3,

4,

5} , Zheng Chen _{1,

2,

3,

4,

5} , Qian Liu _{1,

2,

3,

4,

5}

Affiliation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an etiological agent of the current rapidly growing outbreak of coronavirus disease (COVID-19), which is straining health systems around the world. Disrupting the intermolecular association of SARS-CoV-2 spike glycoprotein (S protein) with its cell surface receptor human angiotensin-converting enzyme 2 (hACE2) has been recognized as a promising therapeutic strategy against COVID-19. The association is a typical peptide-mediated interaction, where the hACE adopts an α1-helix, which can form a two-helix bundle with the α2-helix, to pack against a flat pocket on the S protein surface. Here, we demonstrate that the protein context of full-length hACE plays an essential role in supporting the hACE2 α1-helix recognition by viral S protein. Energetic analysis reveals that the α1-helical peptide (αHP) and also the two-helix bundle peptide (tBP) cannot bind effectively to S protein when they are split from the hACE protein. The context contributes moderately and considerably to the direct readout (DR) and indirect readout (IR) of peptide recognition, respectively. Dynamics simulation suggests that the two free peptides exhibit a large intrinsic disorder without the support of protein context, which would incur a considerable entropy penalty upon binding to S protein. To restore the IR effect lost by splitting peptides from hACE, we herein propose employing hydrocarbon stapling and cyclization strategies to constrain the free αHP and tBP peptides into their native ordered conformations, respectively. The stapling and cyclization are carefully designed in order to avoid influencing the peptide DR effect, which has been demonstrated to improve the peptide binding affinity (but not specificity) to S protein. The stapling/cyclization-imposed conformational constraint can effectively minimize the unfavorable IR effect (i) by reducing the peptide flexibility and entropy cost upon their binding to S protein, and (ii) by helping peptide pre-folding into their native state to facilitate the conformational selection by S protein.

中文翻译：

背景对SARS-CoV-2穗突蛋白对人ACE2衍生肽的分子间识别的贡献：对于改善肽亲和力但不通过优化间接读数来改变肽特异性的影响

严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）是目前迅速增长的冠状病毒疾病（COVID-19）的病原体，该疾病正在全球范围内困扰着卫生系统。破坏SARS-CoV-2穗糖蛋白（S蛋白）与其细胞表面受体人类血管紧张素转化酶2（hACE2）的分子间联系已被认为是针对COVID-19的一种有前途的治疗策略。缔合是典型的肽介导的相互作用，其中hACE采用α1-螺旋，可以与α2-螺旋形成两个螺旋束，以堆积在S蛋白表面的平坦口袋上。在这里，我们证明全长hACE的蛋白质环境在支持hACE2α1-螺旋被病毒S蛋白识别方面起着至关重要的作用。（t BP）从hACE蛋白中分裂出来时，不能与S蛋白有效结合。上下文分别对肽识别的直接读出（DR）和间接读出（IR）起到了适度的作用。动力学模拟表明，两种游离肽在没有蛋白质背景支持的情况下表现出较大的内在紊乱，这将在与S蛋白结合时引起相当大的熵损失。为了恢复通过从hACE分裂肽而丢失的IR效应，我们在本文中建议采用烃类装订和环化策略来限制游离αHP和tBP肽分别变成其天然有序构象。精心设计了装订和环化反应，以避免影响肽DR效应，这种作用已被证明可以改善对S蛋白的肽结合亲和力（但不提高特异性）。装订/环化施加的构象约束可以有效地最小化不利的IR效应（i）通过降低肽与S蛋白结合时的柔韧性和熵代价，以及（ii）帮助肽预折叠成其天然状态以促进S蛋白的构象选择。

更新日期：2020-12-09

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