  Despite being used for decades as stabilizers, amino acids (AAs) remain
mysterious components of many medical and biological formulations. Hypotheses
on their role vary ranging from hydrotropic to protein-specific effects
(stabilization against misfolding). Here, we deduce that AAs possess a new and
broad colloidal property by finding that stabilizing effect of the AAs is
comparable on dispersion of various proteins, plasmid DNA, and non-biological
nanoparticles. The interactions among colloidal particles in dispersion are
carefully evaluated by the second osmotic virial coefficient (B_22) and the
potential of mean force. We propose a theoretical framework that explains the
stabilization as the effect of weakly interacting small molecules with patchy
nanoscale colloids. We validate it through quantitative comparison with
experimental data by comparing equilibrium dissociation constants for
AA/proteins obtained either by fitting the B22 data with this theory or
experimentally. We find excellent quantitative agreement (e.g. proline/lysozyme
1.18 and 2.28 M, respectively) and indeed that the interactions are very weak.
The theory presented implies that (i) charged AAs will be effective only for
proteins of opposite charge; (ii) short peptides composed of n AAs will be as
or more effective than n separate AAs; (iii) any small molecule weakly
interacting with nanoscale colloids that increases the solvation of the surface
will have a stabilizing effect. The experimental evidences corroborate all
three predictions. Much like the ionic strength of the solution is commonly
reported, our results imply that the same should be done for the small
molecules, as they also affect fundamentally colloidal properties. As an
example, we show that AAs vary the cloud point of a lysozyme solution by as
much as 4 K.
