  Protein-protein interactions (PPI) differ when measured in test tubes and
cells due to the complexity of the intracellular environment. Free amino acids
(AAs) and their derivatives constitute a significant fraction of the
intracellular volume and mass. Recently, we have found that AAs have a general
property of rendering protein dispersions more stable by reducing the net
attractive part of PPI. Here, we study the effects on PPI of different AA
derivatives, AA mixtures, and short peptides. We find that all the tested AA
derivatives modulate PPI in solution as well as AAs. Furthermore, we show that
the modulation effect is additive when AAs form mixtures or are bound into
short peptides. Therefore, this study demonstrates the universal effect of a
class of small molecules (i.e. AAs and their biological derivatives) on the
modulation of PPI and provides insights into rationally designing biocompatible
molecules for stabilizing protein interactions and consequently tuning protein
functions.
