This article examines three techniques for rapidly assessing the electrostatic contribution of individual amino acids to the stability of protein-protein complexes. Whereas the energetic minimization of modeled oligomers may yield more accurate complexes, we examined the possibility that simple modeling may be sufficient to identify amino acids that add to or detract from electrostatic complementarity. The three methods evaluated were (a) the elimination of entire side chains (e.g., glycine scanning), (b) the elimination of the electrostatic contribution from the atoms of a side chain, called nullification, and (c) side chain structure prediction using SCWRL4. These techniques generate models in seconds, enabling large-scale mutational scanning. We evaluated these techniques on the SMAD2/SMAD4 heterotrimer, whose formation plays a crucial role in antitumor pathways. Many studies have documented the clinical and structural effect of specific mutations on trimer formation. Our results describe how glycine scanning yields more specific predictions, although nullification may be more sensitive, and how side chain structure prediction enables the identification of uncharged-to-charge mutations.
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