Research Summary
Stabilizing Proteins Against Aggregation
Proteins in solution have a tendency to aggregate
due to favorable free energy for the reduction of
solvent-accessible area, particularly of hydrophobic
groups. Proteins in the aggregated state generally
do not have the same biological activity as proteins
in the native state, they can often be immunogenic,
and my even have acute toxic effects in vivo. This
is an especially grave problem for the pharmaceutical
industry, where it is desired to store proteins
at the highest possible concentration over long
periods of time. Thus it is essential to develop
strategies for preventing aggregation to extend
the shelf life of therapeutic proteins.
One such strategy is the use of “neutral crowder”
additives. In this case, there is the potential
for a “gap effect” to arise if the additive is significantly
larger than the primary solvent. This effect is
analogous to osmotic stress. The large additive
will be excluded from solvating the gap between
protein molecules for steric reasons, thus increasing
the free energy of the protein-protein encounter
complex. If the additive does not interact with
the isolated protein any differently than water,
the primary effect is an increase in the activation
energy of the protein association reaction, thus
slowing the rate of aggregation. |
