Can We AlphaFold Our Way Out of the Next Pandemic?

Abstract

The announcement of the outstanding performance of AlphaFold 2 in the CASP 14 protein structure prediction competition came at the end of a long year defined by the COVID-19 pandemic. With an infectious organism dominating the world stage, the developers of Alphafold 2 were keen to play their part, accurately predicting novel structures of two proteins from SARS-CoV-2. In their blog post of December 2020, they highlighted this contribution, writing "we've also seen signs that protein structure prediction could be useful in future pandemic response efforts". So, what role does structural biology play in guiding vaccine immunogen design and what might be the contribution of AlphaFold 2?

Keywords: AlphaFold; structure-guided immunogenicity design; vaccine.

Graphical abstract

Figure 1

Respiratory syncytial virus as a paradigm of structure-guided design. The F protein of the respiratory syncytical virus undergoes a dramatic conformational change from its metastable pre-fusion conformation (PDB: 4JHW) to its post-fusion conformation (PDB: 3RRR). The F protein is a trimer with the three subunits shown in red, orange and yellow. The D25 monoclonal antibody is shown in blue. The most effective neutralising monoclonal antibodies target the pre-fusion conformation of the F protein and structure-guided vaccine design processes involve either modifications to stabilise the pre-fusion conformation or to design small de novo proteins which specifically present the epitopes for neutralising antibodies.

Figure 2

Structure-guided vaccinology of the coronavirus spike. The structure of the closed confirmation of the SARS-CoV-2 spike (PDB: 6VSB) is shown with the three subunits of the trimer in different shades of blue. The 2P mutations (residues 986 and 987) are highlighted in pink, with an arrow pointing to one of these copies. These mutations stabilise the spike in the pre-fusion conformation and are included in a number of the effective COVID-19 vaccines.

Figure 3

Structure-guided vaccinology for blood stage malaria. The PfRH5 protein is a promising antigen for a vaccine to prevent malaria caused by Plasmodium falciparum. Structures of PfRH5 (yellow) bound to human monoclonal antibodies such as 004 (red) and 016 (blue) (PDB: 6RCU) revealed flexible loops in PfRH5 which could be removed to ablate epitopes for non-neutralising antibodies. Structural insight also allowed the design of thermally stabilised versions of PfRH5, improving physiochemical properties.