Initiation of Medial Calcification: Revisiting Calcium\nIon Binding to Elastin

Pathological calcification of elastin,\na key connective tissue\nprotein in the medial layers of blood vessels, starts with the binding\nof calcium ions. This Mini-Review focuses on understanding how calcium\nions interact with elastin to initiate calcification at a molecular\nlevel, and emphasizes water’s critical role in mediating this\ninteraction. In the past decade, great strides have been made in understanding\nand modeling ion-specific hydration and its effects on biomolecule\ninteractions. However, these advances have been largely absent from\nour understanding of elastin calcification. Historically, charge-neutral\nbackbone carbonyls and negatively charged carboxyl groups have been\nproposed as elastin’s calcium binding sites. Recently, tropoelastin’s\nonly four carboxyl groups have been identified as binding sites from\nclassical molecular dynamics (MD). While carboxyl groups have a much\nhigher affinity for binding calcium ions than backbone carbonyls,\nconflicting evidence persists for both functional group’s importance\nin elastin calcification. This can be attributed to the fact that\ndivalent ions strongly polarize water, leading to a hydration shell\nthat shields electrostatic forces. The hydration shell surrounding\nboth a calcium ion and either of the proposed binding sites must be\ndisplaced to enable binding. Providing our own extended X-ray absorption\nfine structure (EXAFS) data and complementary simulations, we discuss\nthe potential structures of calcium binding in elastin and review\nprior knowledge regarding the relative importance of the two proposed\nbinding sites.