BioByte 143: Predicting Structure of Large Protein Complexes, Restoring Naive T-cell Production, Large Scale Reading/Writing of Neuronal Activity, and Valuing Drug Programs with Tripartite Models
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What we read
Papers
Scalable prediction of symmetric protein complex structures [Yu et al., bioRxiv, November 2025]
Why it matters: Researchers from the startup EndoFold built Cosmohedra, a physics-based model that assembles predicted structures of large, symmetric proteins at a fraction of the time previously required. This model unlocks biological inquiry and drug discovery into this class of previously expensive-to-model proteins - including building new drugs that disrupt viral complexes.
AlphaFold has been a breakthrough in protein structure prediction and downstream drug discovery, but it has its constraints. Chief among these is the large memory requirement: the transformers underpinning AlphaFold2/3 require memory that quadratically scales with sequence length (O(L2)), meaning that large proteins and protein complexes do not fit within a single AlphaFold prediction window without significant loss of accuracy or feasibility.
To tackle the problem of structure prediction for large proteins and complexes, the team at EndoFold take advantage of a convenient pattern in biology: protein symmetry. Many large complexes are just symmetric assemblies of smaller monomeric proteins! Take, for example, the Drosophila dArc2 capsid, a retrovirus-like capsid protein co-opted for neuronal cell-to-cell mRNA-based communication. The whole virus-like protein is an assembly of 240 identical Arc2 proteins, each 193 residues large. (Sidenote: Why does nature do this? One explanation is that it is genomically cheaper to encode a single monomer of 579 nucleotides, rather than explicitly encoding a full complex totaling 138,960 nucleotides.)
While AlphaFold can’t model the full complex, it generally can model the monomers of these large, symmetric proteins well! EndoFold builds on this foundation by constructing a physics-based assembly model Cosmohedra that uses true and predicted monomer structures and assembles them into symmetric complexes based on their symmetry class. To build the structure of the dArc2 capsid, for example, they assemble the predicted
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