11/20/2023 0 Comments Nature bingo set![]() ![]() Finally, screening for alternate states in protein families without known fold-switching identified a putative alternate state for the oxidoreductase Mpt53 in M. To test AF-Cluster’s sensitivity to point mutations, we designed and experimentally verified a set of 3 mutations predicted to flip KaiB from Rhodobacter sphaeroides from the ground to the fold-switched state. We used nuclear magnetic resonance (NMR) spectroscopy to confirm a surprising AF-Cluster prediction: a cyanobacteria KaiB variant is stabilized in the opposite state than the more widely-studied variant. Using this method, AF-Cluster, we investigated the evolutionary distribution of predicted structures for the metamorphic protein KaiB 5, and found that predictions of both conformations were distributed in clusters across the KaiB-family. ![]() We demonstrate that clustering a multiple sequence alignment (MSA) by sequence similarity enables AF2 to sample alternate states of known metamorphic proteins with high confidence. However, a protein’s biological function often depends on multiple conformational substates 2, and disease-causing point mutations often cause population changes within these substates 3,4. AlphaFold2 (AF2) 1 has revolutionized structural biology by accurately predicting single structures of proteins. ![]()
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