Decoding nonspecific interactions from natureElectronic supplementary information (ESI) available: Additional information on the sensitivity to the surface cutoff, details on the method of identifying interior surface residues, the glycine-serine sequence pair, the definition of interaction energy, a description of the calculation of error bars for each figure, and SPR sensograms. See DOI: 10.1039/c2sc21135a

The interactions which govern chemical processes may be broadly categorized into specific interactions, high activity for a certain target molecule, and nonspecific interactions, low activity for all targets. Despite their ubiquity in biology and chemistry, nonspecific interactions are generally overlooked and a fundamental understanding of nonspecific interactions is lacking. Molecular chaperones are large protein complexes which have evolved to resist nonspecific interactions. Their interior surface resists binding to thousands of types of misfolded proteins. Proteins found in the cytoplasm, a crowded environment with many spurious binding targets, are another example. These proteins have evolved high selectivity and stability despite nonspecific interactions. Using structural bioinformatics, we have studied the interiors of molecular chaperones from five species and examined the surface chemistry of 1162 proteins, categorized by if they are present in the cytoplasm or extracellular space. A better understanding of how nature resists nonspecific interactions is key for the chemistry of materials, surfaces, and particles which must remain stable in complex environments. The abundance of amino acids, their interactions, their hydration, and sequence patterns were compared in these two systems, molecular chaperones and proteins surfaces. Striking similarities were found and trends were identified as the system environments became harsher. Peptide based mimics were synthesized to test the conclusions. This, in turn, has led to the design of new stealth compounds and a deeper understanding of nonspecific interactions. The interactions which govern chemical processes may be broadly categorized into specific interactions, high activity for a certain target molecule, and nonspecific interactions, low activity for all targets.