Defne Gorgun, Muyun Lihan, Karan Kapoor, and Emad Tajkhorshid.
Binding mode of SARS-CoV2 fusion peptide to human cellular
membrane.
Biophysical Journal, 120:191a, 2021.
GORG2021-ET
Infection of human cells by the SARS-CoV2 relies on its
binding to a specific receptor and subsequent fusion of the viral and
host cell membranes. The fusion peptide (FP), a short peptide segment
in the spike protein, plays a central role in the initial penetration
of the virus into the host cell membrane, followed by the fusion of
the two membranes. Here, we use an array of molecular dynamics (MD)
simulations taking advantage of the Highly Mobile Membrane Mimetic
(HMMM) model, to investigate the interaction of the SARS-CoV2 FP with
a lipid bilayer representing mammalian cellular membranes
at an atomic level, and to characterize the membrane-bound form of the
peptide. Six independent systems were generated by changing the
initial positioning and orientation of the FP with respect to the
membrane, and each system was simulated in five independent replicas,
each for 300ns. In 73% of the simulations, the FP reaches a stable,
membrane-bound configuration where the peptide deeply penetrated into
the membrane. Clustering of the results reveals three major membrane
binding modes (binding modes 1-3) where binding mode 1 populates over
half of the data points. Taking into account the sequence conservation
among the viral FPs and the results of mutagenesis studies
establishing the role of specific residues in the helical portion of
the FP in membrane association, the significant depth of penetration
of the whole peptide, and the dense population of the respective
cluster, we propose that the most deeply inserted membrane-bound form
(binding mode 1) represents more closely the biologically relevant
form. Analysis of FP-lipid interactions shows the involvement of
specific residues, previously described as the "fusion active core
residues", in membrane binding. Taken together, the results shed light
on a key step involved in SARS-CoV2 infection with potential
implications in designing novel inhibitors.
