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Concentration-Dependent Structural Transition of the HIV-1 gp41 MPER Peptide into α-Helical Trimers

Sai Chaitanya Chiliveri1, John M Louis1, Ad Bax1

  • 1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.

Angewandte Chemie (International Ed. in English)
|September 11, 2020
PubMed

Insights

The membrane proximal external region (MPER) of HIV-1 gp41 transitions from an unfolded monomer to an alpha-helical trimer. This structural change is concentration-dependent and influenced by solution conditions, impacting antibody recognition.

Area of Science:

  • Structural biology
  • Virology
  • Biochemistry

Background:

  • The membrane proximal external region (MPER) of HIV-1 gp41 is a key target for broadly neutralizing antibodies.
  • Previous studies reported varying structures for the MPER depending on experimental conditions.

Purpose of the Study:

  • To elucidate the solution structure and conformational dynamics of the HIV-1 gp41 MPER fragment.
  • To understand the factors governing MPER structural transitions and their implications for antibody binding.

Main Methods:

  • Equilibrium dialysis and thermodynamic analysis to determine association constants and thermodynamic parameters.
  • Circular dichroism, NMR spectroscopy (13Cα chemical shifts, NOE), and hydrogen exchange mass spectrometry to characterize MPER structure.

Main Results:

  • The MPER fragment exists in an aqueous solution monomer-trimer equilibrium with a micromolar association constant.
  • Thermodynamic analysis indicates hydrophobically driven association, favored by D2O and increased ionic strength.
  • MPER undergoes a concentration-dependent structural transition from an unfolded monomer to an α-helical trimer.

Conclusions:

  • The MPER adopts an α-helical trimeric structure at higher concentrations, driven by hydrophobic interactions.
  • These findings provide insights into antibody recognition mechanisms of the MPER during HIV-1 fusion.
  • Understanding MPER structural dynamics is crucial for developing effective HIV-1 therapeutics.
Keywords:
HIV-1 gp41MPERNMR spectroscopyhelical structuresmonomer-trimer equilibrium

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