Permeation Mechanisms of Calcium and Phosphate Ions into the Collagen Fibril Hole Zone

Abstract Collagen fibrils provide a templating scaffold for calcium phosphate deposition during bone mineralization, yet the molecular mechanism underlying the penetration of calcium and phosphate ions from the bulk phase into the collagen fibrils remains poorly understood. For the first time, we quantify the thermodynamic feasibility of the potential ion penetration pathways across the collagen fibril and successfully identify that the pathways preferentially permitting Ca2+ passage are not energetically favorable for HPO42– entry and vice versa. We confirm that the observed selective ion permeation across collagen fibril pathways cannot be explained by size exclusion alone, and electrostatic attraction from charged amino acid residues emerges as the primary driving force for ion migration. Free energy decompositions demonstrate that water-induced contributions hinder ion entry, whereas the ion–collagen interactions provide the dominant favorable driving force that compensates for the solvent penalty to promote permeation. This dominant contribution mainly arises from electrostatic interactions between the ions and oppositely charged amino acid residues, thereby directing ion entry into the collagen hole zone. This study provides key insights into the role of collagen fibrils in biomineralization for building theoretical foundations on the design of bone repair and implant materials.