Abstract
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.
Highlights
Proteoglycans (PGs) are vital constituents of cellular membranes and extracellular matrices, where they confer tissue mechanical properties, facilitate constitutive cell−cell interactions, and are implicated in neurodegeneration, arthritis, and cancer.[1−4] Human PGs, such as bikunin and decorin,[5,6] comprise a core protein plus one or more covalently linked glycosaminoglycan (GAG) polymers, which possess functionally important patterns of postsynthetic modification
Porcine dermatan sulfate (DS) was estimated to contain a mix of GalNAc 4-O
It has been shown that accurate spatiotemporal PG models, including complex heterogeneous GAG sequences, can be constructed by abstracting glycosidic linkage and pyranose ring atomic motions from multi-μs fine-grained simulations
Summary
Proteoglycans (PGs) are vital constituents of cellular membranes and extracellular matrices, where they confer tissue mechanical properties, facilitate constitutive cell−cell interactions, and are implicated in neurodegeneration, arthritis, and cancer.[1−4] Human PGs, such as bikunin and decorin,[5,6] comprise a core protein plus one or more covalently linked glycosaminoglycan (GAG) polymers, which possess functionally important patterns of postsynthetic modification. Atomic resolution crystallographic studies have been limited to either the protein core (e.g., for small leucine-rich repeat PGs13−15) or isolated GAG components (e.g., fiber X-ray scattering data for chondroitin-4-sulfate[16]). Modeling offers an avenue to progress, but accurate fine-grained simulations (i.e., including all atoms and water solvent) have been restricted to oligosaccharides and short sub-μs time scales (notwithstanding approaches that distort biologically important kinetics[17]). This limitation has, to some extent, been recently overcome by the use of application-specific integrated circuits and graphics processing units, which have enabled unbiased multi-μs computational studies.[18,19]. This limitation has, to some extent, been recently overcome by the use of application-specific integrated circuits and graphics processing units, which have enabled unbiased multi-μs computational studies.[18,19] application of fine-grained simulations to even small PGs will remain out of reach for the foreseeable future
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