Complexation of peptide epitopes with G4-PAMAM dendrimer through ligand diffusion molecular dynamic simulations.
J Mol Graph Model
; 96: 107514, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-31877401
ABSTRACT
Peptide epitopes from HIV-1 gp120 have been used to block the gp120-CD4 complex, whereas their poor absorbable or immunogenic properties prevent them from coupling to generation four polyamidoamine (PAMAM-G4) dendrimers. PAMAM-G4 are synthetic nanoparticles that are relatively nontoxic and nonimmunogenic have been employed as nanocarriers. In a previous study, two peptide epitopes (ABC and PGV04) from gp120 located at the protein-protein interface of the gp120-CD4 complex were identified through protein-protein dissociation. Then, their complexation with G4-PAMAM was evaluated through experimental and theoretical approaches, revealing a stoichiometry of 18/9 for G4-PAMAM and ABC or PGV04, respectively, providing important information that can be used to gain insight into the structural and energetic basis of the molecular binding of these G4-PAMAM-peptide systems. In this contribution, we performed ligand diffusion molecular dynamic simulations (LDMDSs) using 1.5 µs combined with the molecular mechanics generalized Born surface area (MMGBSA) approach, a strategy that successfully reproduced experimentally encapsulation on PAMAM-G4-ligand complexes, to explore the mechanism through which ABC and PGV04 are encapsulated by PAMAM-G4 under neutral and acid conditions. Our results reproduce the reported PAMAM-G4-peptide complex stoichiometry, revealing a slower peptide delivery at neutral conditions and a spontaneous release under acidic conditions. LDMDSs show that several peptides can reach stable G4-PAMAM complexes at neutral pH, and only a few are able to encapsulate on dendrimers without impacting dendrimer sphericity. Energetic analysis exploring different generalized Born models revealed that the ABC peptide has better binding properties than PGV04.
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01-internacional
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MEDLINE
Assunto principal:
Dendrímeros
Idioma:
En
Revista:
J Mol Graph Model
Ano de publicação:
2020
Tipo de documento:
Article