Establishing a Framework of Using Residue-Residue Interactions in Protein Difference Network Analysis.

Detailed understanding of interactions between amino acid residues is critical in using promising difference network analysis approaches to map allosteric communication pathways. Using experimental data as benchmarks, we scan values of two essential residue-residue contact parameters: the distance cutoff (dc) and the cutoff of residue separation in sequence (nc). The optimal dc = 4.5 Å is revealed, which defines the upper bound of the first shell of residue-residue packing in proteins, whereas nc is found to have little effects on performance. We also develop a new energy-based contact method for network analyses and find an equivalency between the energy network using the optimal energy cutoff ec = 1.0 kBT and the structure network using dc = 4.5 Å. The simple 4.5-Å contact method is further shown to have comparable prediction accuracy to a contact method using amino acid type-specific distance cutoffs and chemical shift prediction-based methods. This study provides necessary tools in mapping dynamics to functions.