The discovery of a putative allosteric site in SARS-CoV-2 spike protein by an integrated structural/dynamical approach.

SARS-CoV-2 has caused the largest pandemic of the XXI (COVID-19), threatening the life and economy of all countries in the world. Finding therapies and vaccines to mitigate or even fight this sanitary and health threat is among the most important challenges of biomedical sciences in the century. To build up a long-term strategy to fight not only SARS-CoV-2 but also other possible future threat from coronaviruses, it is mandatory to understand the molecular mechanisms underlying the virus action. The viral entry and thus infectivity is based on the formation of the complex of the SARS-CoV-2 spike protein with the angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein can trace the path to develop allosteric drugs to weaken spike-ACE2 interaction and, thus, to reduce the viral infectivity. In this work we present results of the application of the Protein Contact Network (PCN) paradigm together with SEPAS (affinity by flexibility) and Perturbation Response Scanning (PRS) based on Elastic Network modes to the complex SARS-CoV spike - ACE2 relative to both 2003 SARS and the recent SARS-CoV-2. All the adopted analysis paradigms converge toward a specific region, present in both structures, that is predicted to act as allosteric site modulating the binding of the spike protein with ACE2.