In Silico Investigations of Calcium Phosphate Mineralization in Extracellular Vesicles

Calcification in bone, cartilage, and cardiovascular tissues involves the release of specialized extracellular vesicles (EVs) that promote mineral nucleation. The small size of the EVs, however, makes molecular level studies difficult, and consequently uncertainty exists on the role and function of these structures in directing mineralization. The lack of mechanistic understanding associated with the initiators of ectopic mineral deposition has severely hindered the development of potential therapeutic options. Here, we used multiscale molecular dynamics simulations to investigate the calcification within the EVs. Results show that Ca²⁺-HPO₄^2- and phosphatidylserine complexes facilitate the early nucleation. Use of coarse-grained simulations allows investigations of Ca²⁺-PO₄^3- nucleation and crystallization in the EVs. Systematic variation in the ion-to-water ratio shows that the crystallization and growth strongly depend on the enrichment of the ions and dehydration inside the EVs. Our investigations provide insights into the role of EVs on calcium phosphate mineral nucleation and growth in both physiological and pathological mineralization.