ImmunityBio Simulates SARS-CoV-2 Spike Protein Binding Using Molecular Dynamics
ImmunityBio, a privately-held immunotherapy company, announced the results of a highly detailed computer-based molecular dynamics (MD) simulation, conducted in collaboration with Microsoft Corporation, that allowed visualization of the behavior of the SARS-CoV-2 “spike” protein. The simulation provides an explanation for the virulence of the COVID-19 virus and has the potential to give researchers a roadmap for developing tools to disable the virus and future mutated versions.
“These findings demonstrate the extraordinary evolutionary adaption of the spike protein to readily bind and infect host cells,” said Patrick Soon-Shiong, MD, Chairman and CEO of ImmunityBio. “We will use this important new data to inform our COVID-19 drug discovery program, advance the ongoing clinical trials of our vaccine candidate, and enhance our ability to understand threats posed by future versions of the SARS-CoV-2 virus, which has become a pressing issue with the spread of novel highly infectious SARS-CoV-2 variants.”
The simulations indicate that the spike protein of the virus has evolved to be a nearly ideal fit for the ACE2 receptor—a viral “key” that engages perfectly with the “lock” that, when opened, allows the virus to insert its genetic material into the cell. Even in its free, unbound state, spike RBD assumes a three-dimensional shape that requires almost no adjustment to bind efficiently with host ACE2. This precision fit is what ensures the virus is almost always successful in infecting target cells in the human respiratory tract. Notably, the simulations showed the precise shape of the portion of the protein that binds to ACE2, the receptor binding domain.
The simulations were unique in that interactions between the spike protein and the receptor it targets to gain entry to human cells, known as human angiotensin-converting enzyme 2 (ACE2), were modeled for two milliseconds. This offers scientists a view that is approximately 10,000 times longer than most previous simulations, providing greater confidence in the results.
“Even though we hope that widespread vaccination will greatly reduce COVID-19, we know that not all individuals will get vaccinated and that the first-generation vaccines may not provide complete protection for all,” said Dr. Soon-Shiong. “ImmunityBio is developing new therapeutics to treat infected individuals, and many of these therapeutic approaches will benefit from the findings revealed in this simulation.”
Researchers are eager to visualize the way the spike protein interacts with ACE2, as well as the molecular profile of the RBD area, as this is what launches an infection. With the information revealed in the ImmunityBio molecular dynamic simulation, researchers have two potential paths forward to create therapies to disarm COVID-19. First, the simulation provides an experimental roadmap for the creation of molecules that would mimic ACE2 in the body—in effect, “dummy” locks to which the virus would bind instead of living cells. The simulation also provides key information that may be used to create therapies that change the shape of the RBD region so the viral “key” no longer fits the cellular “lock.”
Microsoft Corporation and NantWorks provided the computing resources for the simulation, which provided detailed views of the most likely natural shape (conformation) of the spike protein. The manuscript and a video detailing the findings of the ImmunityBio molecular dynamic simulation studies is available on preprint server bioRxiv and is concurrently undergoing scientific peer-review for publication.