In a recent Science paper, Sarel Fleishman et al. report the de-novo computational design of a protein interface to specifically target and tightly bind a surface patch of the flu hemaglutinin protein. We interview Sarel to get the insights from behind the scenes and the outlook for this exciting approach.
Traditionally, computational protein design efforts have been directed at calculating a single sequence predicted to fold to a particular target structure. Recently, however, a number of conceptual generalizations have been pursued, ranging from the use of backbone flexibility, off-rotamer side chain flexibility, negative design, multi-body potentials, conformational free energy, and prediction of sequence profiles. Below I present our state-of-the-art research whose goal is to understand how protein sequences are optimized to be compatible with binding multiple partners with high affinity. – By Menachem Fromer.
About a month ago Yose Widjaja posted a question to the pdb-l mailing list:
” Suppose you have two pdb files of two proteins you suspect interact with each other. What existing approaches exist out there that can tell you whether these two proteins interact, based on the structural information alone? “
In a research published at Cell, Skerker et al. performs a computational co-variation analysis on a dataset of two-component system sequences. This results in a set of putative specificity determining residues. The authors then demonstrate how they can successfully use these to modulate Histidine Kinase-Response Regulator interactions both in-vitro and in-vivo. By Nir London