| Popis: |
Self-assembling peptides have emerged as promising candidates for a wide range of applications, ranging from drug delivery vehicles to scaffolds for tissue engineering and catalytic nanomaterials. In particular, amyloid-like β- sheets formed by histidine-rich peptides have recently shown both hydrolytic activity and structural modularity in response to single amino acid mutations, raising interest in the structure- sequence dependence of their catalytic activity. An explanation for why certain amyloid-forming peptides lose their catalytic function could aid in the development of new peptides with improved activities. In this study, we investigated how changes at the sequence level affect Zn(II) coordination and the formation of supramolecular structures, leading to an obstruction of potential active sites in aggregated states. A series of molecular dynamics simulations (MD) were performed with six linear and cyclic peptides: Ac-IHIHINI-Am, Ac-IHINIHI-Am, cyclo-[IHIHINIE], cyclo-[IHINIHIE], cyclo- [IhIHINIE], and cyclo-[IhIhINIE] to assess whether the increase of rigidity influences the metal coordination. These peptides were simulated in solutions with different ZnCl2 concentrations using all-atom MD with CHARMM36m force fields in GROMACS to determine the effects of Zn(II) on aggregation, the different aggregation patterns of the six peptides, and the correct coordination of Zn(II), which is essential for catalytic activity. To confirm the aggregation time, Zn(II) coordination, and formation of self-assembled structures, we measured the center-of-mass distance of individual peptides, the pairwise distances of Zn(II) ions and histidines and analyzed clustering in systems containing 6 and 24 peptide monomers. Our results indicate that the presence of Zn(II)ions affects the peptide aggregation behavior and that changes in sequence composition, chirality, or cyclization of peptides affect the aggregation/self-assembly propensity. Furthermore, we demonstrate the utility of center- of-mass distance measurements as a quantitative measure of peptide aggregation that can be used to complement simulation-based approaches. In conclusion, we noticed that the changes of amino acid disposition in the sequence that strongly affect supramolecular behavior also led to disruption/loss of peptide function. |
