title: An unexpected way forward: towards a more accurate and rigorous protein-protein binding affinity scoring function by eliminating terms from an already simple scoring function.
abstract: A fundamental and unsolved problem in biophysical chemistry is the development of a computationally simple, physically intuitive, and generally applicable method for accurately predicting and physically explaining protein-protein binding affinities from protein-protein interaction (PPI) complex coordinates. Here, we propose that the simplification of a previously described six-term PPI scoring function to a four term function results in a simple expression of all physically and statistically meaningful terms that can be used to accurately predict and explain binding affinities for a well-defined subset of PPIs that are characterized by (1) crystallographic coordinates, (2) rigid-body association, (3) normal interface size, and hydrophobicity and hydrophilicity, and (4) high quality experimental binding affinity measurements. We further propose that the four-term scoring function could be regarded as a core expression for future development into a more general PPI scoring function. Our work has clear implications for PPI modeling and structure-based drug design.
authors.affiliation: a ChemModeling LLC , Suite 101, 500 Huber Park Ct, Weldon Spring , MO 63304 , USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Swanson
authors.affiliation: b CMD Bioscience , 5 Science Park , New Haven , CT 06511 , USA.|c Department of Chemistry , Sacred Heart University , 5151 Park Ave, Fairfield , CT 06825 , USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Audie
mesh_terms: D001667:Binding, Competitive; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010455:Peptides; D011506:Proteins
keywords: biophysical chemistry; molecular modeling; molecular recognition; protein–protein interaction; structural informatics