Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Sci Adv. 2021 Apr 16;7(16). doi: 10.1126/sciadv.abf3671. Print 2021 Apr.
The COVID-19 (coronavirus disease 2019) pandemic underwent a rapid transition with the emergence of a dominant viral variant (from the "D-form" to the "G-form") that carried an amino acid substitution D614G in its "Spike" protein. The G-form is more infectious in vitro and is associated with increased viral loads in the upper airways. To gain insight into the molecular-level underpinnings of these characteristics, we used microsecond all-atom simulations. We show that changes in the protein energetics favor a higher population of infection-capable states in the G-form through release of asymmetry present in the D-form inter-protomer interactions. Thus, the increased infectivity of the G-form is likely due to a higher rate of profitable binding encounters with the host receptor. It is also predicted to be more neutralization sensitive owing to enhanced exposure of the receptor binding domain, a key target region for neutralizing antibodies. These results are critical for vaccine design.
COVID-19（冠状病毒病 2019）大流行随着一种主要病毒变异体（从“D 型”到“G 型”）的出现而迅速转变，该变异体在其“刺突”蛋白中携带一个氨基酸取代 D614G。G 型在体外更具传染性，与上呼吸道中的病毒载量增加有关。为了深入了解这些特征的分子水平基础，我们使用了微秒全原子模拟。我们表明，通过释放 D 型互变异构体相互作用中存在的不对称性，蛋白质能量的变化有利于 G 型中更多具有感染能力的状态。因此，G 型的传染性增加可能是由于与宿主受体的有利结合遭遇率更高。由于受体结合域的暴露增强，它也被预测更容易受到中和，受体结合域是中和抗体的关键靶区。这些结果对于疫苗设计至关重要。
