Apr 4, 2014

A generative algorithm for de novo design of proteins with diverse pocket structures

BioRxiv : the Preprint Server for Biology
Chunyu BaiYuehui Ma


To create new enzymes and biosensors from scratch, precise control over the structure of small molecule binding sites is of paramount importance, but systematically designing arbitrary protein pocket shapes and sizes remains an outstanding challenge. Using the NTF2-like structural superfamily as a model system, we developed a generative algorithm for creating a virtually unlimited number of de novo proteins supporting diverse pocket structures. The generative algorithm was tested and refined through feedback from two rounds of large scale experimental testing, involving in total, the assembly of synthetic genes encoding 7896 generated designs and assessment of their stability on the yeast cell surface, detailed biophysical characterization of 64 designs, and crystal structures of 5 designs. The refined algorithm generates proteins that remain folded at high temperatures and exhibit more pocket diversity than naturally occurring NTF2-like proteins. We expect this approach to transform the design of small molecule sensors and enzymes by enabling the creation of binding and active site geometries much more optimal for specific design challenges than is accessible by repurposing the limited number of naturally occurring NTF2-like p...Continue Reading

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Mentioned in this Paper

Biochemical Pathway
Microarray Analysis
Structure of Beta Cell of Islet
Post-Transcriptional Regulation
RNA, Untranslated
Insulin/Insulin Receptor Signaling Pathway
Regulation of Biological Process
Sequence Determinations, RNA

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