Structural basis of calcium and phosphatidylserine binding annexin V and beyond
Abstract
Annexins are an important family of proteins that play key roles in crucial biological contexts, sharing the common property of binding membrane phospholipids in a Ca2+-dependent manner. For its importance as a prototype in structural studies and for its potential as a diagnostic and therapeutic tool, annexin A5 (AnxA5) deserves a special role within this family. Using a variety of computational methods, including PDB surveys, molecular docking studies, classical molecular dynamics, and metadynamics, we here extensively investigated the atomic-level basis of phospholipid recognition by AnxA5. In this scenario, we initially provided a comprehensive description of the calcium-binding protein. These data were also used to develop an effective approach to identify protein metal sites and their relative affinities by combining the predictive power of AlphaFold 3 with metadynamics, without relying on any prior structural information. Interestingly, the predicted Ca2+ affinities for the predicted binding sites are consistent with their occupancy in crystallographic structures, as deduced from a survey of the Protein Data Bank. Furthermore, we describe the possible binding modes of phosphatidylserine analogs to annexin V in both its monomeric and trimeric states. Finally, we derived some structural fingerprints of the phosphatidylserine-AnxA5 recognition whose occurrence was analysed across all available PDB structures of mammalian annexins.
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