From sample to structure. 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)