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AlphaFold2 对 SARS-CoV-2 刺突奥密克戎 JN.1、KP.2 和 KP.3 变体构象集合的建模和分子动力学模拟:结合能突变分析揭示 ACE2 亲和力的上位驱动因素和抗体耐药性逃逸热点。

AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance.

机构信息

Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.

Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.

出版信息

Viruses. 2024 Sep 13;16(9):1458. doi: 10.3390/v16091458.


DOI:10.3390/v16091458
PMID:39339934
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11437503/
Abstract

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth and fitness due to convergent evolution of functional hotspots. These hotspots operate in tandem to optimize both receptor binding for effective infection and immune evasion efficiency, thereby maintaining overall viral fitness. The lack of molecular details on structure, dynamics and binding energetics of the latest FLiRT and FLuQE variants with the ACE2 receptor and antibodies provides a considerable challenge that is explored in this study. We combined AlphaFold2-based atomistic predictions of structures and conformational ensembles of the SARS-CoV-2 spike complexes with the host receptor ACE2 for the most dominant Omicron variants JN.1, KP.1, KP.2 and KP.3 to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and computations of binding affinities, we identified binding energy hotspots and characterized the molecular basis underlying epistatic couplings between convergent mutational hotspots. The results suggested the existence of epistatic interactions between convergent mutational sites at L455, F456, Q493 positions that protect and restore ACE2-binding affinity while conferring beneficial immune escape. To examine immune escape mechanisms, we performed structure-based mutational profiling of the spike protein binding with several classes of antibodies that displayed impaired neutralization against BA.2.86, JN.1, KP.2 and KP.3. The results confirmed the experimental data that JN.1, KP.2 and KP.3 harboring the L455S and F456L mutations can significantly impair the neutralizing activity of class 1 monoclonal antibodies, while the epistatic effects mediated by F456L can facilitate the subsequent convergence of Q493E changes to rescue ACE2 binding. Structural and energetic analysis provided a rationale to the experimental results showing that BD55-5840 and BD55-5514 antibodies that bind to different binding epitopes can retain neutralizing efficacy against all examined variants BA.2.86, JN.1, KP.2 and KP.3. The results support the notion that evolution of Omicron variants may favor emergence of lineages with beneficial combinations of mutations involving mediators of epistatic couplings that control balance of high ACE2 affinity and immune evasion.

摘要

最近一波源自 BA.2 和 BA.2.86 的 SARS-CoV-2 奥密克戎变体由于功能热点的趋同进化而表现出更好的病毒生长和适应性。这些热点协同作用,优化了受体结合以实现有效感染和免疫逃逸效率,从而保持了整体病毒适应性。由于缺乏关于最新的 FLiRT 和 FLuQE 变体与 ACE2 受体和抗体结合的结构、动力学和结合能的分子细节,这在很大程度上是一个挑战,本研究对此进行了探索。我们将基于 AlphaFold2 的结构原子预测和 SARS-CoV-2 刺突复合物的构象组合与宿主受体 ACE2 相结合,用于最主要的奥密克戎变体 JN.1、KP.1、KP.2 和 KP.3,以研究趋同进化热点在平衡 ACE2 结合和抗体逃逸中的作用机制。通过使用 Spike 蛋白残基的基于集合的突变扫描和结合亲和力计算,我们确定了结合能热点,并描述了趋同突变热点之间上位性耦合的分子基础。结果表明,在 L455、F456 和 Q493 位置的趋同突变位点之间存在上位性相互作用,这些位点既能保护又能恢复 ACE2 结合亲和力,同时赋予有益的免疫逃逸能力。为了研究免疫逃逸机制,我们对 Spike 蛋白与几类抗体的结合进行了基于结构的突变分析,这些抗体对 BA.2.86、JN.1、KP.2 和 KP.3 的中和活性受损。结果证实了实验数据,即含有 L455S 和 F456L 突变的 JN.1、KP.2 和 KP.3 可以显著降低 1 类单克隆抗体的中和活性,而 F456L 介导的上位性效应可以促进随后 Q493E 变化的趋同,以挽救 ACE2 结合。结构和能量分析为实验结果提供了一个理由,表明结合不同结合表位的 BD55-5840 和 BD55-5514 抗体可以保留对所有研究的 BA.2.86、JN.1、KP.2 和 KP.3 变体的中和效力。结果支持这样一种观点,即奥密克戎变体的进化可能有利于出现具有有利突变组合的谱系,这些突变涉及控制高 ACE2 亲和力和免疫逃逸平衡的上位性耦合的介质。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/d16a57d97a05/viruses-16-01458-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/f133fa961d19/viruses-16-01458-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/b79cb4547dfe/viruses-16-01458-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/0ea7df18f7e3/viruses-16-01458-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/9c2098aaf8d4/viruses-16-01458-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/dfd98480708b/viruses-16-01458-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/bb83e7ff21b0/viruses-16-01458-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/c16a9db0cfdc/viruses-16-01458-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/19cd133681c8/viruses-16-01458-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/12492eae842b/viruses-16-01458-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/d16a57d97a05/viruses-16-01458-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/f133fa961d19/viruses-16-01458-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/dd52908adffc/viruses-16-01458-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/a22f0071d33e/viruses-16-01458-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/b79cb4547dfe/viruses-16-01458-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/0ea7df18f7e3/viruses-16-01458-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/9c2098aaf8d4/viruses-16-01458-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/dfd98480708b/viruses-16-01458-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/bb83e7ff21b0/viruses-16-01458-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/c16a9db0cfdc/viruses-16-01458-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/19cd133681c8/viruses-16-01458-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/12492eae842b/viruses-16-01458-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c414/11437503/d16a57d97a05/viruses-16-01458-g012.jpg

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[3]
Comparable immune escape capacity between KP.2 and other SARS-CoV-2 variants in the central Chinese population after the first COVID-19 booster.

Sci Rep. 2025-5-22

[4]
Biophysics of SARS-CoV-2 spike protein's receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights.

Biophys Rev. 2025-3-8

[5]
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[7]
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[8]
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本文引用的文献

[1]
AI-Predicted Protein Deformation Encodes Energy Landscape Perturbation.

Phys Rev Lett. 2024-8-30

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