Home » Protein structure determination using metagenome sequence data

Protein structure determination using metagenome sequence data

Top: Researchers gathering samples from Great Boiling Spring in Nevada. Left: a snapshot of aligned metagenomic sequences. Each row is a different sequence (the different colors are the different amino acid groups). Each position (or column) is compared to all other positions to detect patterns of co-evolution. Bottom: the strength of the top co-evolving residues is shown as blue dots, these are also shown as colored lines on the structure above. The goal is to make a structure that makes as many of these contacts as possible. Right: a cartoon of the protein structure predicted. The protein domain shown is from Pfam DUF3794, this domain is part of a Spore coat assembly protein SafA. (Image of Great Boiling Spring by Brian Hedlund, UNLV. Protein structure and composite image by Sergey Ovchinnikov, UW)

Despite decades of work by structural biologists, there are still ~5200 protein families with unknown structure outside the range of comparative modeling. We show that Rosetta structure prediction guided by residue-residue contacts inferred from evolutionary information can accurately model proteins that belong to large families and that metagenome sequence data more than triple the number of protein families with sufficient sequences for accurate modeling. We then integrate metagenome data, contact-based structure matching, and Rosetta structure calculations to generate models for 614 protein families with currently unknown structures; 206 are membrane proteins and 137 have folds not represented in the Protein Data Bank. This approach provides the representative models for large protein families originally envisioned as the goal of the Protein Structure Initiative at a fraction of the cost.

Additional Links: