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Two new computational approaches are described to aid in the design of new peptide-based drugs by evaluating ensembles of protein structures from their dynamics and through the assessing of structures using empirical contact potential. These approaches build on the concept that conformational variability can aid in the binding process and, for disordered proteins, can even facilitate the binding of more diverse ligands. This latter consideration indicates that such a design process should be less restrictive so that multiple inhibitors might be effective. The example chosen here focuses on proteins/peptides that bind to hemagglutinin (HA) to block the large-scale conformational change for activation. Variability in the conformations is considered from sets of experimental structures, or as an alternative, from their simple computed dynamics; the set of designe peptides/small proteins from the David Baker lab designed to bind to hemagglutinin, is the large set considered and is assessed with the new empirical contact potentials. 

Abstract Protein sequence matching presently fails to identify many structures that are highly similar, even when they are known to have the same function. The high packing densities in globular proteins lead to interdependent substitutions, which have not previously been considered for amino acid similarities. At present, sequence matching compares sequences based only upon the similarities of single amino acids, ignoring the fact that in densely packed protein, there are additional conservative substitutions representing exchanges between two interacting amino acids, such as a small‐large pair changing to a large‐small pair substitutions that are not individually so conservative. Here we show that including information for such pairs of substitutions yields improved sequence matches, and that these yield significant gains in the agreements between sequence alignments and structure matches of the same protein pair. The result shows sequence segments matched where structure segments are aligned. There are gains for all 2002 collected cases where the sequence alignments that were not previously congruent with the structure matches. Our results also demonstrate a significant gain in detecting homology for “twilight zone” protein sequences. The amino acid substitution metrics derived have many other potential applications, for annotations, protein design, mutagenesis design, and empirical potential derivation.