  Most of the ongoing projects aimed at the development of specific therapies
and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main
target [1-3]. The binding of the spike protein with the ACE2 receptor (ACE2) of
the host cell constitutes the first and key step for virus entry. During this
process, the receptor binding domain (RBD) of the S protein plays an essential
role, since it contains the receptor binding motif (RBM), responsible for the
docking to the receptor. So far, mostly biochemical methods are being tested in
order to prevent binding of the virus to ACE2 [4]. Here we show, with the help
of atomistic simulations, that external electric fields of easily achievable
and moderate strengths can dramatically destabilise the S protein, inducing
long-lasting structural damage. One striking field-induced conformational
change occurs at the level of the recognition loop L3 of the RBD where two
parallel beta sheets, believed to be responsible for a high affinity to ACE2
[5], undergo a change into an unstructured coil, which exhibits almost no
binding possibilities to the ACE2 receptor (Figure 1a). Remarkably, while the
structural flexibility of S allows the virus to improve its probability of
entering the cell, it is also the origin of the surprising vulnerability of S
upon application of electric fields of strengths at least two orders of
magnitude smaller than those required for damaging most proteins. Our findings
suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus
without further biochemical processing. Moreover, the effect could be used for
infection prevention purposes and also to develop technologies for in-vitro
structural manipulation of S. Since the method is largely unspecific, it can be
suitable for application to mutations in S, to other proteins of SARS-CoV-2 and
in general to membrane proteins of other virus types.
