Structural prediction of chimeric immunogens to elicit targeted antibodies against betacoronaviruses
Simpson, J.; Kasson, P. M.
Show abstract
Betacoronaviruses pose an ongoing pandemic threat. Antigenic evolution of the SARS-CoV-2 virus has shown that much of the spontaneous antibody response is narrowly focused rather than broadly neutralizing against even SARS-CoV-2 variants, let alone future threats. One way to overcome this is by focusing the antibody response against better-conserved regions of the viral spike protein. Here, we present a design approach to predict stable chimeras between SARS-CoV-2 and other coronaviruses, creating synthetic spike proteins that display a desired conserved region and vary other regions. We leverage AlphaFold to predict chimeric structures and create a new metric for scoring chimera stability based on AlphaFold outputs. We evaluated 114 candidate spike chimeras using this approach. Top chimeras were further evaluated using molecular dynamics simulation as an intermediate validation technique, showing good stability compared to low-scoring controls. Experimental testing of five predicted-stable and two predicted-unstable chimeras confirmed 5/7 predictions, with one intermediate result. This demonstrates the feasibility of the underlying approach, which can be used to design custom immunogens to focus the immune response against a desired viral glycoprotein epitope.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Design of a symmetry-broken tetrahedral protein cage by a method of internal steric occlusion 95%
- The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain 94%
- The importance of input sequence set to consensus-derived proteins and their relationship to reconstructed ancestral proteins 94%
Similar papers in this journal
Similar papers in this journal
- Targeted in situ cross-linking mass spectrometry and integrative modeling reveal the architectures of Nsp1, Nsp2, and Nucleocapsid proteins from SARS-CoV-2 95%
- Raf promotes dimerization of the Ras G-domain with increased allosteric connections 95%
- Mechanistic Insights into Dengue Virus Inhibition by a Clinical Trial Compound NITD-688 94%
Similar papers in this journal
- Using machine learning to detect coronaviruses potentially infectious to humans 96%
- Natural variants in SARS-CoV-2 S protein pinpoint structural and functional hotspots; implications for prophylaxis and therapeutics strategies 95%
- Potential Neutralizing Antibodies Discovered for Novel Corona Virus Using Machine Learning 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.