Sequence of the\nSARS-CoV-2 Spike Transmembrane Domain\nEncodes Conformational Dynamics

The homotrimeric SARS-CoV-2 spike protein enables viral\ninfection\nby undergoing a large conformational transition, which facilitates\nthe fusion of the viral envelope with the host cell membrane. The\nspike protein is anchored to the SARS-CoV-2 envelope by its transmembrane\ndomain (TMD), composed of three TM helices, each contributed by one\nof the protomers of spike. Although the TMD is known to be important\nfor viral fusion, whether it is a passive anchor of the spike or actively\npromotes fusion remains unknown. Specifically, it is unclear if the\nTMD and its dynamics facilitate the prefusion to postfusion conformational\ntransition of the spike. Here, we computationally study the dynamics\nand self-assembly of the SARS-CoV-2 spike TMD in homogeneous POPC\nand cholesterol containing membranes. Atomistic simulations of a long\nTM helix-containing protomer segment show that the membrane-embedded\nsegment bobs, tilts and gains and loses helicity, locally thinning\nthe membrane. Coarse-grained multimerization simulations using representative\nTM helix structures from the atomistic simulations exhibit diverse\ntrimer populations whose architecture depends on the structure of\nthe TM helix protomer. While a symmetric conformation reflects the\nsymmetry of the resting spike, an asymmetric TMD conformation could\npromote membrane fusion through the stabilization of a fusion intermediate.\nTogether, our simulations demonstrate that the sequence and length\nof the SARS-CoV-2 spike TM segment make it inherently dynamic, that\ntrimerization does not abrogate these dynamics and that the various\nobserved TMD conformations may enable viral fusion.