Detailed atomistic investigation of aggregation and interaction of teriparatide in aqueous media

Teriparatide (TPTD), a recombinant peptide used in osteoporosis treatment, exhibits self-association that may lead to immunogenicity and reduced therapeutic efficacy. To investigate its aggregation behavior, we performed molecular dynamics simulations of systems containing 1, 5, and 10 TPTD molecules in water, assessing concentration-dependent effects. Structural and dynamic properties were analyzed using root-mean-square deviation, free energy landscapes, secondary structure probabilities, and Kirkwood-Buff integrals derived from radial distribution functions. The simulations reveal key intermolecular interactions and conformational preferences that drive TPTD self-assembly. Water-mediated hydrogen bonding and hydrophobic contacts were found to modulate aggregation, with notable structural compaction at higher concentrations. These findings provide mechanistic insight into TPTD aggregation and offer guidance for minimizing immunogenic risks in peptide-based therapeutics.