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The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex
Bidisha Nandy1, Suman Saurabh, Anil Kumar Sahoo
1Center for Condensed Matter Theory, Department of Physics, Indian Institute of Science, Bangalore, India. maiti@physics.iisc.ernet.in.
Nanoscale
|October 24, 2015
Summary
The dendrimer SPL7013 weakens the HIV-1 gp120-CD4 complex, hindering virus entry. This topical microbicide candidate shows promise by destabilizing the virus-cell interaction crucial for infection.
Area of Science:
- Biophysics
- Virology
- Materials Science
Background:
- The poly (l-lysine)-based SPL7013 dendrimer is a topical microbicide candidate targeting HIV-1 entry.
- The precise mechanism by which SPL7013 inhibits R5 HIV-1, a variant significant in transmission, is not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism of SPL7013's action against R5 HIV-1.
- To investigate the interaction between SPL7013, R5 gp120, and the CD4 receptor.
Main Methods:
- Molecular docking simulations to predict binding modes of SPL7013 to R5 gp120.
- Fully atomistic and steered molecular dynamics (MD) simulations to analyze binding affinities and complex stability.
- Calculation of binding energies and dissociation forces for the gp120-CD4 complex with and without SPL7013.
Main Results:
- SPL7013 binds strongly to R5 gp120 within the gp120-CD4 complex but weakly to gp120 alone.
- SPL7013 binding does not occlude the CD4 binding site but significantly weakens the gp120-CD4 complex.
- Steered MD simulations revealed that SPL7013 lowers the force required to dissociate the gp120-CD4 complex, accelerating its rupture.
Conclusions:
- SPL7013 compromises the stability of the R5 gp120-CD4 complex.
- This destabilization potentially prevents sufficient gp120-CD4 complex formation at the virus-cell interface, thereby blocking HIV-1 entry.
