Sequence of the SARS-CoV-2 Spike Transmembrane Domain Encodes Conformational Dynamics

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