Knot or not? Identifying unknotted proteins in knotted families with sequence-based Machine Learning model

Varování

Publikace nespadá pod Filozofickou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

Autoři	SIKORA Maciej KLIMENTOVÁ Eva UCHAL Dawid ŠRÁMKOVÁ Denisa PERLINSKA Agata P NGUYEN Mai Lan KORPACZ Marta MALINOWSKA Roksana NOWAKOWSKI Szymon RUBACH Pawel ŠIMEČEK Petr SULKOWSKA Joanna I
Rok publikování	2024
Druh	Článek v odborném periodiku
Časopis / Zdroj	Protein Science
Fakulta / Pracoviště MU	Středoevropský technologický institut
Citace
www	https://onlinelibrary.wiley.com/doi/10.1002/pro.4998
Doi	http://dx.doi.org/10.1002/pro.4998
Klíčová slova	AlphaFold; deep learning; knotted proteins; protein topology; SPOUT family proteins
Popis	Knotted proteins, although scarce, are crucial structural components of certain protein families, and their roles continue to be a topic of intense research. Capitalizing on the vast collection of protein structure predictions offered by AlphaFold (AF), this study computationally examines the entire UniProt database to create a robust dataset of knotted and unknotted proteins. Utilizing this dataset, we develop a machine learning (ML) model capable of accurately predicting the presence of knots in protein structures solely from their amino acid sequences. We tested the model's capabilities on 100 proteins whose structures had not yet been predicted by AF and found agreement with our local prediction in 92% cases. From the point of view of structural biology, we found that all potentially knotted proteins predicted by AF can be classified only into 17 families. This allows us to discover the presence of unknotted proteins in families with a highly conserved knot. We found only three new protein families: UCH, DUF4253, and DUF2254, that contain both knotted and unknotted proteins, and demonstrate that deletions within the knot core could potentially account for the observed unknotted (trivial) topology. Finally, we have shown that in the majority of knotted families (11 out of 15), the knotted topology is strictly conserved in functional proteins with very low sequence similarity. We have conclusively demonstrated that proteins AF predicts as unknotted are structurally accurate in their unknotted configurations. However, these proteins often represent nonfunctional fragments, lacking significant portions of the knot core (amino acid sequence).