AlphaKnot: server to analyze entanglement in structures predicted by AlphaFold methods

Niemyska, Wanda; Rubach, Paweł; Greń, Bartosz Ambroży; Nguyen, Mai Lan; Garstka, Wojciech; Silva, Fernando Bruno da; Rawdon, Eric J.; Sułkowska, Joanna I.

doi:10.1093/nar/gkac388

Cited by 25 publications

(33 citation statements)

References 13 publications

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“…This study presented the first crystal structure of the double knotted protein, CnTrmD-Tm1570; however, high-confidence proteins containing double knots are provided AlphaFold, and their structural analyses are deposited in AlphaKnot. 1 Thus, understanding the structure and function of knotted proteins can provide important insights into how proteins work and how they can be regulated. Overall, it still needs to be fully understood how knotted protein affects degradation, and more research is needed to clarify the relationship between these two processes.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…30 The topology, and knot core location of each structure selected from the simulation was determined using an implementation of the Alexander polynomial defined in the AlphaKnot database. 1,31 Degradation Time and Tube Model…”

Section: Molecular Dynamics Topology Detectionmentioning

confidence: 99%

“…These speculations were strongly enforced by the AI predictions made by AlphaFold, which contained several structures containing composite knots, some of which were of high fidelity. 1 Perlinska et al put the attention towards members of the SPOUT superfamily, the most well-known group of deeply trefoil (3 1 ) knotted proteins. They found four possible arrangements of domains in SPOUT family, which could lead to double knotted structures.…”

Section: Introductionmentioning

confidence: 99%

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First crystal structure of double knotted protein TrmD-Tm1570 – inside from degradation perspective

Silva

Lewandowska

Kluza

et al. 2023

Preprint

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Herein, we present the first crystal structure of a double knotted protein TrmD-Tm1570 from Calditerrivibrio nitroreducens, as well the X-ray structure of each subdomain. The protein consists of two domains TrmD and Tm1570, each embedding a single trefoil knot, which can function on their own. TrmD-Tm1570 forms a compact homodimeric complex. This protein represents one of 296 possible doubly knotted proteins from SPOUT family. Based on TrmD-Tm1570 from Calditerrivibrio nitroreducens we show that a double knotted protein can be fully degraded by the ClpXP degradation system, as well as its individual domains. We used numerical simulations to explain the difference in the speed of degradation. The derived kinetic parameters for the degradation process are comparable to the experimental data found for unknotted polypeptide chains

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Dynamics Topology Detectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

First crystal structure of double knotted protein TrmD-Tm1570 – inside from degradation perspective

Silva

Lewandowska

Kluza

et al. 2023

Preprint

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“…They are also available in Alpha-Knot database alongside with knotted proteins of 20 other proteomes at https://alphaknot.cent.uw.edu.pl. (Niemyska et al, 2022) After careful evaluation, we concluded that over 75% of the models containing knots are artifacts. However, most of the previously known knotted human proteins were correctly predicted, which shows that AlphaFold is capable of modeling structures with complicated topology (see Table S1 for details about all proteins we classified as knotted).…”

Section: Introductionmentioning

confidence: 96%

AlphaFold predicts novel human proteins with knots

et al. 2023

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The fact that proteins can have their chain formed in a knot is known for almost 30 years. However, as they are not common, only a fraction of such proteins is available in the Protein Data Bank. It was not possible to assess their importance and versatility up until now because we did not have access to the whole proteome of an organism, let alone a human one. The arrival of efficient machine learning methods for protein structure prediction, such as AlphaFold and RoseTTaFold, changed that. We analyzed all proteins from the human proteome (over 20,000) determined with AlphaFold in search for knots and found them in less than 2% of the structures. Using a variety of methods, including homolog search, clustering, quality assessment, and visual inspection, we determined the nature of each of the knotted structures and classified it as either knotted, potentially knotted, or an artifact, and deposited all of them in a database available at: https://knotprot.cent.uw.edu.pl/alphafold. Overall, we found 51 credible knotted proteins (0.2% of human proteome). The set of potentially knotted structures includes a new complex type of a knot not reported in proteins yet. That knot type, denoted 63 in mathematical notation, would necessitate a more complex folding path than any knotted protein characterized to date.

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AlphaFold predicts the most complex protein knot and composite protein knots

et al. 2022

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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.

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AlphaKnot: server to analyze entanglement in structures predicted by AlphaFold methods

Cited by 25 publications

References 13 publications

First crystal structure of double knotted protein TrmD-Tm1570 – inside from degradation perspective

First crystal structure of double knotted protein TrmD-Tm1570 – inside from degradation perspective

AlphaFold predicts novel human proteins with knots

AlphaFold predicts the most complex protein knot and composite protein knots

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