All‐atom simulations of the trimeric spike protein of SARS‐CoV‐2 in aqueous medium: Nature of interactions, conformational stability and free energy diagrams for conformational transition of the protein

Abstract

The spike protein of SARS‐CoV‐2 exists in two major conformational states, namely the ‘open’ and ‘closed’ states which are also known as the ‘up’ and ‘down’ states, respectively. In its open state, the receptor binding domain (RBD) of the protein is exposed for binding with ACE2, whereas the spike RBD is inaccessible to ACE2 in the closed state of the protein. In the current work, we have performed all‐atom microsecond simulations of the full‐length trimeric spike protein solvated in explicit aqueous medium with an average system size of ~0.7 million atoms to understand the molecular nature of intra‐ and inter‐chain interactions, water‐bridged interactions between different residues that contribute to the stability of the open and closed states of the protein, and also the free energy landscape for transition between the open and closed states of the protein. We have also examined the changes of such interactions that are associated with switching from one state to the other through both unbiased and biased simulations at all‐atom level with total run length of 4 μs. Interestingly, after about 0.8 μs of unbiased molecular dynamics run of the spike system in the open state, we observed a gradual transition of the monomeric chain (B) from open to its partially closed or down state. Initially the residues at the interface of chain B RBD in the open state spike protein were at non‐hydrogen‐bonding distances from the residues of chain C RBD. However, the two RBDs gradually came closer and finally the residue S459 of the RBD of chain B made a hydrogen bond with F374 of chain C in the last 200 ns of the simulation along with formation of a few more hydrogen bonds involving other residues. Since no transition from closed to the open state of the protein is observed in the present 1 μs unbiased simulation of the closed state protein, the current study seems to suggest that the closed conformational state is preferred for the spike protein of SARS‐CoV‐2 in aqueous medium. Furthermore, calculations of the free energy surface of the conformational transition from open (up) to the closed (down) state using a biased simulation method reveal a free energy barrier of ~3.20 kcal/mol for the transition of RBD from open to the closed state, whereas the barrier for the reverse process is found to be significantly higher.

Switching Go̅-Martini for Investigating Protein Conformational Transitions and Associated Protein–Lipid Interactions

“…Therefore, some systems cannot be simulated properly yet, such as the spike protein, in which N-glycans play an important role. 64 − 66 Still, we were able to reproduce the open-to-closed transition of the spike protein in the absence of N-glycans, and the results are in line with previous all-atom simulations ( Figure S8 ). 66 , 67 …”

“… 64 − 66 Still, we were able to reproduce the open-to-closed transition of the spike protein in the absence of N-glycans, and the results are in line with previous all-atom simulations ( Figure S8 ). 66 , 67 …”

“…64−66 Still, we were able to reproduce the open-to-closed transition of the spike protein in the absence of N-glycans, and the results are in line with previous all-atom simulations (Figure S8). 66,67 Although the approach has demonstrated success in simulating conformational transitions of proteins, it is important to acknowledge the limitations of our method. First, the switching Go ̅ -Martini method needs structures of two known states of multiple-state proteins to sample the conformational transitions between these states.…”

Omicron Coronavirus: pH-Dependent Electrostatic Potential and Energy of Association of Spike Protein to ACE2 Receptor

“…As is known, when the S-trimer binds to the ACE2 receptor, one of the three S chains (the one contacting ACE2) undergoes structural changes obtaining so-called open conformation [ 61 , 62 ]; this structural transition is initiated by the binding with the hACE2 receptor [ 45 , 63 ]; it is an order of magnitude slower than the first phase of the binding [ 37 ] and can depend on the pH of the medium [ 64 ]; the energetic barrier for the reverse transition to close state is much higher [ 65 ]. Besides the experiments with isolated S-protein in solution, the experiments with S-protein incorporated in artificial virions also reveal that the three monomers in the free S-trimer are in closed conformation [ 66 ].…”