Continuous flexibility analysis of SARS-CoV-2 spike prefusion structures

Abstract

Using a new consensus-based image-processing approach together with principal component analysis, the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state have been analysed. These studies revealed concerted motions involving the receptor-binding domain (RBD), N-terminal domain, and subdomains 1 and 2 around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. It is shown that in this data set there are not well defined, stable spike conformations, but virtually a continuum of states. An ensemble map was obtained with minimum bias, from which the extremes of the change along the direction of maximal variance were modeled by flexible fitting. The results provide a warning of the potential image-processing classification instability of these complicated data sets, which has a direct impact on the interpretability of the results.

Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM

“…S5I), in line with our local resolution data (Fig. S5D) and a recent report (40). However, the motion directions of the associated ACE2-RBD in S-ACE2 complex are divergent to some extend from those of the up RBD in S-open, implying that ACE2 binding could alter the conformational dynamics of the up RBD and potentially the allosteric coordination of S1 subunits.…”

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

“…4, unclear if any additional conformational states other than those with either all three RBD domains in the closed state or only one RBD open state are biologically relevant. Specifically, Yurkovetskiy et al [44] observed an occupancy for states with two or three RBD domains in the open conformation, but these were not observed by Gobeil et al [30] and Xiong et al [34] or taken into consideration in several other structural studies [20][21][22][23][24]. As such, we employ the two-state model shown in Figure 2 [30] and Xiong et al [34].…”

“…Several aspects of the dynamics of the Spike protein are being currently studied, with a range of particular goals: to evaluate the docking of small molecules to the RBD domain [19], to search for alternative target binding-sites for vaccine development [20], to understand residue-residue interactions and their effects on conformational plasticity [21] and to investigate the flexibility of different domains in particular conformational states [22].…”

Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein**

“…Moreover, in two of the three replicate simulations of cholesterol bound to the open spike, cholesterol in the site formed by the open subunit (site 3) migrates to an alternative site in the open structure. The proximity of this alternative site to the hinge region, which is important for conformational changes of the spike between the locked and open forms, [30, 36] suggests a possible mechanism by which cholesterol binding at this position may affect the dynamics and preferred conformation of the spike RBD, potentially stabilizing a form which presents the RBD for ACE2 binding.…”