Dynamical asymmetry exposes 2019-nCoV prefusion spike

Susmita Roy

To monitor the transition between the 'S1-head-up' and the 'S1-head-down' states for each monomer with the trimeric interactions, a large pool of unbiased longtime trajectories generated where multiple occurrences of up and down states for each monomer have been sampled. We employ a reaction coordinate, Q, the fraction of the native contact (19, 27) corresponding to the inter-chain contacts associated with the 'S1-head-up' and the 'S1-head-down' states. A typical trajectory plot of Q extracted from the equilibrium simulation of the trimeric prefusion spike clearly shows the hopping between different conformational states as hypothesized earlier (Fig. 3A) . Furthermore, the dynamic transitions between the two major asymmetric states (1up-2down: Q S1-head-down ≈0.45 and 2up-down: Q S1-head-down ≈0.15) are evident in the Q-trajectory. Analysis of all the simulations yields the 2-D free energy landscape of the trimeric spike protein of SARS-CoV-2 ( Fig 3B) with its all possible conformations. The conformations corresponding to the minima of the free energy landscape are shown in Fig.3C . The temperature dependence of conformational transition indicates that the configurational entropy and enthalpy compensation results in the enhanced population of the asymmetric 1up-2down to 2up-1down conformations ( Fig S4) . While the predominant population of the 1up-2down state is consistent with the recent Cryo-EM data, (7) (Movie S1, S2) the other asymmetric structure (2up-1down) emerges as a best binding epitope for CR3022 (an antibody collected from convalescent SARS patients) according to a recent antibody recognition study of SARS-CoV-2 S (14). author/funder. All rights reserved. No reuse allowed without permission.