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Updated: Aug 10, 2025
Identification of Functional Protein Regions Through Chimeric Protein Construction
Published on: January 8, 2019
Structural prediction of chimeric immunogens to elicit targeted antibodies against betacoronaviruses
Jamel Simpson1, Peter M Kasson1,2,3
1Program in Biophysics and Department of Biomedical Engineering, Box 800886, Charlottesville VA 22908.
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.
Insights
Scientists designed synthetic coronavirus spike proteins to elicit a broader antibody response. This approach uses computational methods to predict stable protein designs, aiming to improve vaccines against current and future pandemic threats.
Area of Science:
- Virology
- Immunology
- Computational Biology
Background:
- Betacoronaviruses, including SARS-CoV-2, present a continuous pandemic risk.
- Spontaneous antibody responses to SARS-CoV-2 are often narrowly focused, limiting effectiveness against variants and future threats.
- Targeting conserved regions of the viral spike protein could yield broader neutralizing antibodies.
Purpose of the Study:
- To develop a computational method for designing stable chimeric spike proteins.
- To create synthetic immunogens that display conserved viral epitopes.
- To focus the immune response against critical, conserved regions of coronaviruses.
Main Methods:
- Leveraging AlphaFold for predicting chimeric protein structures.
- Developing a novel stability scoring metric based on AlphaFold predictions.
- Evaluating 114 candidate spike chimeras computationally.
- Validating top candidates using molecular dynamics simulations.
- Experimental testing of predicted stable and unstable chimeras.
Main Results:
- The computational approach successfully predicted stable chimeric spike proteins.
- Molecular dynamics simulations supported the stability of top-ranked designs.
- Experimental validation confirmed the accuracy of 5 out of 7 predictions for chimera stability.
- The study demonstrated the feasibility of designing custom immunogens.
Conclusions:
- The developed design approach is effective for creating stable chimeric spike proteins.
- This method can be used to engineer immunogens for focused antibody responses.
- The strategy holds promise for developing next-generation vaccines against coronaviruses.
