How can macromolecular crowding affect protein stability ?

The interior of cells is a crowded environment, this can make molecules
in cells behave in radically different ways than in test-tube assays.
Therefore, the study of biochemical processes under realistically
crowded conditions is very important, since these conditions are a
ubiquitous property of all cells and crowding may be essential for
the efficient operation of metabolism. Notably, the size of such effect
is non-linear, so macromolecules are much more strongly affected than
are small molecules as amino acids. Most likely, it is due to the
fact that high concentrations of macromolecules reduce the volume
of solvent available for other molecules in the solution, which has
the result of increasing their effective concentrations. In particular,
the importance of crowding in protein folding is of great interest
in biophysics, once the crowding effect can accelerate the folding
process, given that a compact folded protein will occupy less volume
than an unfolded protein chain. However, crowding can reduce the yield
of correctly folded protein by increasing protein aggregation.

Then, we try to answer the question above by showing that all those
aforementioned complex interactions can be well-described by a straightforward
generalization of a simple Ising-like model, previously proposed by
Bakk and H?ye to account for protein folding under the influence of
a polar solvent. There proteins are described in a close analogy with
a one-dimensional homopolymer, where relevant degrees of freedom are
ascribed by contact maps built from protein residues. Thus, closed
contacts are assigned a binding energy while open contacts present
several configurations of equal (zero) energy. Additionally, we have
introduced a new long-range cooperative/competitive interaction term
that properly models inter-protein interactions (crowding). As an
outcome the model exhibits both cold and warm unfolding, which are
properly affected by the crowded environment as already verified experimentally
for several small globular proteins.