AlphaFold predicts the most complex protein knot and composite protein knots.

Abstract

The computer artificial intelligence system AlphaFold has recently predicted previously unknown three‐dimensional structures of thousands of proteins. Focusing on the subset with high‐confidence scores, we algorithmically analyze these predictions for cases where the protein backbone exhibits rare topological complexity, that is, knotting. Amongst others, we discovered a 71‐knot, the most topologically complex knot ever found in a protein, as well several six‐crossing composite knots comprised of two methyltransferase or carbonic anhydrase domains, each containing a simple trefoil knot. These deeply embedded composite knots occur evidently by gene duplication and interconnection of knotted dimers. Finally, we report two new five‐crossing knots including the first 51‐knot. Our list of analyzed structures forms the basis for future experimental studies to confirm these novel‐knotted topologies and to explore their complex folding mechanisms.