The human touch: Utilizing AlphaFold 3 to analyze structures of endogenous metabolons

Computational structural biology aims to accurately predict biomolecular complexes with AlphaFold 3 spearheading the field. However, challenges loom for structural analysis, especially when complex assemblies such as the pyruvate dehydrogenase complex (PDHc), which catalyzes the link reaction in cellular respiration, are studied. PDHc subcomplexes are challenging to predict, particularly interactions involving weaker, lower-affinity subcomplexes. Supervised modeling, i.e., integrative structural biology, will continue to play a role in fine-tuning this type of prediction (e.g., removing clashes, rebuilding loops/disordered regions, and redocking interfaces). 3D analysis of endogenous metabolic complexes continues to require, in addition to AI, precise and multi-faceted interrogation methods.