Distinct Thermal Response of SARS-CoV-2 Spike Proteins S1 and S2 by Coarse-Grained Simulations

Large-scale computer simulations were employed to investigate the conformational response of the spike protein components S1 and S2 using a coarse-grained model. Temperature was systematically varied to assess the balance between stabilizing residue–residue interactions and thermal fluctuations. The resulting contact profiles reveal distinct segmental reorganization and self-assembly behaviors between S1 and S2. At lower, thermoresponsive temperatures, pronounced segmental globularization occurs in the N-terminal domain (NTD; M153–K202) and receptor-binding domain (RBD; E406–E471) of S1, whereas S2 exhibits alternating regions of high and low contact density. Increasing temperature reduces this segmental globularization, leaving only minor persistence at elevated temperatures. The temperature dependence of the radius of gyration (Rg) further demonstrates the contrasting thermal behaviors of S1 and S2. For S1, Rg increases continuously and monotonically with temperature, reaching a steady-state value approximately 50% higher than that at low temperature. In contrast, S2 displays a non-monotonic response: Rg initially rises to a maximum nearly sevenfold higher than its low-temperature value, then decreases with further temperature increase. Scaling analysis of the structure factor reveals that the globularity of S1 diminishes significantly upon heating, while S2 becomes modestly more compact yet retains its predominantly fibrous character.