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

The COVID-19 pandemic has greatly affected us all, from individuals to the world economy. Whereas great advances have been achieved in record time, a lot remains to be learned about the infection mechanisms of its causative agent, the SARS-CoV-2 coronavirus. The Spike protein interacts with the human angiotensin converting enzyme 2 receptor as part of the viral entry mechanism. To do so, the receptor binding domain (RBD) of Spike needs to be in an open state conformation. Here we utilise coarse-grained normal mode analyses to model the dynamics of the SARS-CoV-2 Spike protein and the transition probabilities between open and closed conformations for the wild type, the D614G mutant as well other variants isolated experimentally. We proceed to perform several possible in silico single mutations of Spike, 17081 in total, to determine positions and specific Spike mutations that may affect the occupancy of the open and closed states. We estimate transition probabilities between the open and closed states from the calculated normal modes. Transition probabilities are employed in a Markov model to determine conformational state occupancies. Our results correctly model a shift in occupancy of the more infectious D614G strain towards higher occupancy of the open state via an increase of flexibility of the closed state and concomitant decrease of flexibility of the open state. Our results also suggest that the N501Y mutation recently observed, drastically increases the occupancy of the open state. We utilize global vibrational entropy differences to select candidate single point mutations that affect the flexibility of the open and closed states and confirm that these lead to shifts in occupancies for the most critical mutations. Among those, we observe a number of mutations on Glycine residues (404, 416, 504) and G252 in particular accepting a number of mutations. Other residues include K417, D467 and N501. This is, to our knowledge, the first use of normal mode analysis to model conformational state transitions and the effect of mutations thereon. The specific mutations of Spike identified here, while still requiring experimental validation, may guide future studies to increase our understanding of SARS-CoV-2 infection mechanisms as well as guide public health in their surveillance efforts.