The
competition for access to space that arises between macromolecules
is the basis of the macromolecular crowding phenomenon, known to modulate
biochemical reactions in subtle ways. Crowding is a highly conserved
physiological condition in and around cells in metazoans, and originates
from a mixture of heterogeneous biomolecules. Here, using collagen
fibrillogenesis as an experimental test platform and ideas from the
theory of nonideal solutions, we show that an entropy-based synergy
is created by a mixture of two different populations of artificial
crowders, providing small crowders with extra volume occupancy when
in the vicinity of bigger crowders. We present the physiological mechanism
by which synergistic effects maximize volume exclusion with the minimum
amount of heterogeneous crowders, demonstrating how the evolutionarily
optimized crowded conditions found <i>in vivo</i> can be
reproduced effectively <i>in vitro</i>