title: Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer.
abstract: The polyamidoamine (PAMAM) dendrimer prevents HIV-1 entry into target cells in vitro. Its mechanism of action, however, remains unclear and precludes the design of potent dendrimers targeting HIV-1 entry. We employed steered molecular dynamics simulations to examine whether the HIV-1 gp120-CD4 complex is a target of PAMAM. Our simulations mimicked single molecule force spectroscopy studies of the unbinding of the gp120-CD4 complex under the influence of a controlled external force. We found that the complex dissociates via complex pathways and defies the standard classification of adhesion molecules as catch and slip bonds. When the force loading rate was large, the complex behaved as a slip bond, weakening gradually. When the loading rate was small, the complex initially strengthened, akin to a catch bond, but eventually dissociated over shorter separations than with large loading rates. PAMAM docked to gp120 and destabilized the gp120-CD4 complex. The rupture force of the complex was lowered by PAMAM. PAMAM disrupted salt bridges and hydrogen bonds across the gp120-CD4 interface and altered the hydration pattern of the hydrophobic cavity in the interface. In addition, intriguingly, PAMAM suppressed the distinction in the dissociation pathways of the complex between the small and large loading rate regimes. Taken together, our simulations reveal that PAMAM targets the gp120-CD4 complex at two levels: it weakens the complex and also alters its dissociation pathway, potentially inhibiting HIV-1 entry.
authors.affiliation: Center for Condensed Matter Theory, Department of Physics, Indian Institute of Science, Bangalore, India.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Nandy
authors.forename: D Hima
authors.initials: DH
authors.lastname: Bindu
authors.forename: Narendra M
authors.initials: NM
authors.lastname: Dixit
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Maiti
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D050091:Dendrimers / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D011073:Polyamines / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000936:Antigen-Antibody Complex; D015704:CD4 Antigens; D050091:Dendrimers; D015699:HIV Envelope Protein gp120; C531249:Poly(amidoamine); D011073:Polyamines; C514793:gp120 protein, Human immunodeficiency virus 1