Glycosaminoglycans (GAGs) are long, linear, highly heterogeneous, and predominantly negatively charged polysaccharides that play important roles in the extracellular matrix and lysosomes. Composed primarily of repeating amino sugar–uronic acid disaccharide units, GAGs can interact with a wide range of protein targets, either in free form or as components of proteoglycans, thereby modulating their structure, dynamics, and function. Their structural heterogeneity, arising largely from variations in sulfation patterns, gives rise to six major classes: chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin, and hyaluronic acid.
Among their protein targets are cathepsins, a family of predominantly cysteine proteases involved in diverse physiological processes, including bone resorption and the maintenance of corneal homeostasis. Dysregulation of cathepsin activity has been associated with a range of pathological conditions, including cancer, osteoporosis, rheumatoid arthritis, and neurodegenerative diseases. Understanding how GAGs regulate cathepsin activity is therefore important for elucidating their physiological roles and may provide a basis for developing new therapeutic strategies.
GAGs can interact not only with mature cathepsins but also with their inactive precursors, procathepsins. Previous studies have suggested that GAG binding can modulate the conformational dynamics of these proteins and thereby regulate their activity through allosteric mechanisms. In mature cathepsins, GAG binding may influence the conformational organization and accessibility of the active site. In procathepsins, in contrast, GAGs may alter the dynamics of the propeptide, which occludes the active site and must be displaced or reorganized during enzyme maturation.
In this presentation, I will discuss recent computational approaches to characterizing the molecular mechanisms underlying GAG-mediated procathepsin maturation. Using molecular dynamics simulations and energy landscape analysis, I will examine how GAG binding influences the conformational dynamics of procathepsins and how these changes may facilitate transitions between inactive and maturation-competent states. Particular emphasis will be placed on connecting atomistic simulations with the underlying conformational energy landscapes and identifying dynamic features that govern the maturation process.
