Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens
During the European Federation for Medicinal Chemistry – International Symposium on Medicinal Chemistry (EFMC-ISMC) 2024, I attended an inspiring lecture by Dr Rommie Amaro from University of California in which she enthusiastically demonstrated the usefulness of molecular dynamics simulations to impact drug and vaccine design by increasing our knowledge of biological targets. Her presentation left me eager to learn more about the research conducted by her group and I was not disappointed when I read their latest Nature Communication on using molecular dynamics to drive the design of SARS-CoV-2 spike S2 immunogens.
As explained in the paper, most COVID-19 vaccines use an engineered version of the spike protein, composed of an S1 domain, responsible for host cell receptor engagement, and an S2 domain, involved in fusion between the viral and host membranes. Understandably, the immunodominant region of the protein is the S1 domain, where a high prevalence of mutations in SARS-CoV-2 variants is observed; meaning many vaccines are more effective on the specific variant they were modelled from. A vaccine composed of only the S2 domain, stabilised in the closed/prefusion state, could be a highly attractive alternative with a decreased susceptibility to resistance.
The Amaro Lab used weighted-ensemble MD simulations, as well as alchemical free energy calculations, to predict that mutating 2 residues to tryptophan would act as “cavity-filling” between the 3 protomers of S2. Their analysis showed an increase in the interactions between the protomers and that more simulation time was required to sample the complex opening, along with a more negative folding free energy; indicating a more stable trimer complex of the double mutant. Indeed, the S2 mutant (named HexaPro-SS-2W) was found to increase cellular expression, thermostability and allow complete cryo-EM characterisation, revealing a closed structure of the trimer complex.