Poster #64 - Connor Pitman

Untangling the role of contiguous hydrophobicity and specialty hydrophobic interactions in residue coevolution

Connor Pitman[1], Anthony Geneva[1,2] Matthew E. B. Hansen[4], Grace Brannigan[1,3] [1] Center for Computational and Integrative Biology, Rutgers-Camden, NJ, 08102 [2] Department of Biology, Rutgers-Camden, NJ, 08102 [3] Department of Physics, Rutgers-Camden, NJ, 08102 [4] Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104

Co-variation of sites across a phylogeny is a powerful means to detect coevolution between positions in a protein sequence. Coevolving pairs have been integrated into many sequence-based studies and methods to identify pairwise interactions that are critical for protein structure and function. Previous research on the amino acids that coevolve has focused on pairs of residues that undergo mechanistically straightforward pairwise interactions, as in electrostatic interactions or disulfide bonds. Less attention has been paid to other kinds of pairwise interactions, particularly between non-aliphatic hydrophobic residues. Additionally, identifying the "local sequence context" surrounding coevolving pairs has been intractable using conventional definitions, as they tend to be found outside of secondary structure elements. Here, we detect coevolving residues across a bacterial dataset composed of ~1600 protein families, and test whether pairs of non-aliphatic amino acids are as likely to be coevolving as oppositely charged pairs or disulfide-bonded pairs. We use blobulation to define the "local hydrophobic context" surrounding coevolving residues, segmenting protein sequences into hydrophobic and polar regions ("blobs"). We have previously found that hydrophobic blobs are enriched disease-causing mutations, despite weak correlation between h-blobs and secondary structure. We find that coevolving pairs undergo a variety of previously uninvestigated pairwise residue interactions, and that they tend to be found in pairs of blobs of the same type - either both in hydrophobic blobs, or both in polar blobs. Additionally, we find that hydrophobic blobs contain many types of coevolving pairs, including polar and oppositely charged residues; while coevolving pairs in polar blobs tend to be limited to oppositely charged and a few other polar residue pairs. Ultimately we observe that coevolving amino acid pairs are associated with certain blob types, indicating the need to account for the hydrophobic context in protein evolutionary studies.