James, A. M.; Schmid, E. W.; Walter, J. C.; Farnung, L.

Nucleosomes are the fundamental unit of eukaryotic chromatin. Diverse factors interact with nucleosomes to modulate chromatin architecture and facilitate DNA repair, replication, transcription, and other cellular processes. An important platform for chromatin binding is the H2A-H2B acidic patch. Here, we used AlphaFold-Multimer to screen over 7000 human proteins for nucleosomal acidic patch binding and identify 41 potential acidic patch binders. We determined the cryo-EM structure of one hit, SHPRH, with the nucleosome at 2.8 angstrom resolution. The structure confirms the predicted acidic patch interaction, reveals that the SHPRH ATPase engages a different nucleosomal DNA location than other SF2-type ATPases, and clarifies the roles of SHPRH\'s domains in nucleosome recognition. Our results illustrate the use of in silico screening as a high throughput method to identify specific interaction types and expands the set of potential acidic patch binding factors. All the screening data is freely available at https://predictomes.org/view/acidicpatch.