Unveiling the G4-PAMAM capacity to bind and protect Ang-(1-7) bioactive peptide

New therapies that allow natural healing processes are required. Such as the endogenous peptide called Angiotensin-(1-7), a safe and eff e drug, which is able to re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular, renal, and pulmonary disease; diabetes; neuropathic pain; Alzheimer and cancer. However, one of the limiting factors for its application is its unfavorable pharmacokinetic profile. In this work, we propose the coupling of Angiotensin-(1-7) to PAMAM dendrimers in order to evaluate the capacity of the nanocarrier to improve isolated peptide features and to gain insight into the structural as well as the energetic basis of its molecular binding. The In Silico tests were performed in acidic and neutral pH conditions as well as amino-terminated and hydroxyl-terminated PAMAM dendrimers. High-rigor computational approaches, such as molecular dynamics and metadynamics simulations were used. We found that, at neutral pH, PAMAM dendrimers with both terminal types are able to interact stably with 3 Angioteinsin-(1-7) peptides through ASP1, TYR4 and PRO7 key aminoacids, however, there are some differences in the binding sites of the peptides. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of HBs are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides.