Proteoglycans and Their Heterogeneous Glycosaminoglycans at the Atomic Scale

Proteoglycan
spatiotemporal organization underpins extracellular
matrix biology, but atomic scale glimpses of this microarchitecture
are obscured by glycosaminoglycan size and complexity. To overcome
this, multimicrosecond aqueous simulations of chondroitin and dermatan
sulfates were abstracted into a prior coarse-grained model, which
was extended to heterogeneous glycosaminoglycans and small leucine-rich
proteoglycans. Exploration of relationships between sequence and shape
led to hypotheses that proteoglycan size is dependent on glycosaminoglycan
unit composition but independent of sequence permutation. Uronic acid
conformational equilibria were modulated by adjacent hexosamine sulfonation
and iduronic acid increased glycosaminoglycan chain volume and rigidity,
while glucuronic acid imparted chain plasticity. Consequently, block
copolymeric glycosaminoglycans contained microarchitectures capable
of multivalent binding to growth factors and collagen, with potential
for interactional synergy at greater chain number. The described atomic
scale views of proteoglycans and heterogeneous glycosaminoglycans
provide structural routes to understanding their fundamental signaling
and mechanical biological roles and development of new biomaterials.