Computational modeling of melanin aggregation
Abstract
Eumelanin is a member of the melanin family. It is a highly heterogeneous polymer composed of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and 5,6-dihydroxyindole (DHI) building blocks, of which DHICA is reported as the more abundant in natural eumelanin while DHI being more common in synthetic eumelanin. In this study, the focus is on the self-assembly of DHI and DHICA eumelanin building blocks in aqueous solutions using computational meth- ods, in particular multi-microsecond molecular dynamics (MD) simulations and density func- tional theory (DFT) calculations.
The results of the MD simulations show that DHI-eumelanin aggregates through nanoscale stacking, and that water molecules are present as a shell around the aggregates. The aggre- gation process is affected by the concentration of the protomolecules in aqueous solutions. The physical mechanisms of stacking were investigated using umbrella sampling (US) and DFT calculations, revealing strong non-covalent stacking interactions between the eumelanin protomolecules. Both the free energy calculations and DFT revealed these strong stacking interactions. The electrostatic potential map provides an explanation and a rationale for the slightly sheared relative orientations and curved shapes of the nanoscale domains.
Regarding the self-assembly of DHICA-eumelanin, water molecules are present inside the large aggregates. Effects of pH on the charged DHICA-eumelanin model were also investi- gated. All DHICA carboxyl groups are negatively charged in acidic to neutral environment (pH 5-7.4). The effect of K+ counterions was also explored, showing that the solubility of the DHICA-eumelanin in its charged form increased, which is possibly due to the charged proto- molecules favoring binding to the K+ counterions rather than aggregating and binding to other protomolecules. Finally, binary mixtures of both charged and uncharged DHICA-eumelanins were investigated, showing aggregation of uncharged DHICA-eumelanins and a few charged DHICA-eumelanins present on the surface of the aggregate and binding to the K+ counteri- ons. Overall, these findings contribute to a better understanding of the structural properties of eumelanin and may aid in the development of new melanin-based materials with enhanced properties.