Dissecting the Black Box of AlphaFold in Protein-Protein Complex Assembly
Li, S.; Mu, Z.; Yan, C.
Show abstract
AlphaFold achieves unprecedented accuracy in modeling protein-protein complexes, yet the principles governing complex assembly remain unclear. Here, we develop a unified interpretability framework for AlphaFold-Multimer and AlphaFold3 to dissect the mechanisms underlying complex formation. We demonstrate that inter-protein coevolution is not a major determinant of assembly. Instead, complex structures are primarily driven by monomer geometry together with interface-level pattern matching between backbone complementarity and residue identities. By visualizing the iterative propagation of distance constraints during inference, we uncover a hierarchical process in which monomer-level constraints are established prior to cross-chain interactions, directly demonstrating that inter-chain geometry is inferred from monomer geometries rather than being encoded by coevolutionary signals. Application to antigen-antibody complexes further reveals that reduced prediction accuracy arises from the non-canonical and structurally plastic nature of immune interfaces, identifying accurate modeling of interface conformations and recognition of atypical antigen-antibody interaction patterns as key bottlenecks for improving immune complex prediction.
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