Urdiciain, A. | Search bioRxiv

bioRxiv2024

Severe deviation in protein fold prediction by advanced AI: a case study

Artificial intelligence (AI) and deep learning are making groundbreaking strides in protein structure prediction. AlphaFold is remarkable in this arena for its outstanding accuracy in modelling proteins fold based solely on their amino acid sequences. In spite of these remarkable advances, experimental structure determination remains critical. Here we report severe deviations (>30 [A]) between the experimental structure of a two-domain protein and its equivalent AI-prediction. These observations are particularly relevant to the relative orientation of the domains within the global protein scaffold. Significant divergence between experimental structures and AI-predicted models echoes the presence of unusual conformations, insufficient training data and high complexity in protein folding that can ultimately lead to current limitations in protein structure prediction.

biochemistry↗

bioRxiv2024

Unusual traits shape the architecture of the Ig ancestor molecule

Understanding the ancestral Ig domains molecular structure and tracing the evolution of Ig-like proteins are fundamental components missing from our comprehension of their evolutionary trajectory and function. We have elucidated the molecular structures of two Ig-like proteins from the evolutionary most ancestral phylum, Porifera, revealing previously unidentified Ig-domain features that highlight the concomitant presence of a novel Ig "Early Variable" (EV)-set in tandem with a C1-set domain. The latter, to our knowledge, has never been reported before in non-vertebrates. The IgV and IgC1 sets and their combination into functional Ig-like receptors are part of the adaptive immune system in higher vertebrates, which allows for highly specific immune responses. These observations in the ancient Porifera phylum could indicate the presence of primitive forms of adaptive immunity or a foundational immune strategy that has been conserved through evolution. By unveiling important clues into the molecular configuration of ancestral Ig domains, these findings challenge and expand our understanding of how immunity has evolved within its current landscape.

evolutionary biology↗