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The flap flexibility in aspartic proteases is crucial for enzyme function. Tyrosine side-chain ring flipping governs flap dynamics, controlling substrate binding pocket access.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Pepsin-like aspartic proteases are crucial enzymes with a flexible flap region essential for catalysis and substrate binding.
  • A conserved tyrosine residue in the flap exists in equilibrium between normal and flipped states.

Purpose of the Study:

  • To investigate the role of tyrosine side-chain dynamics in flap flexibility and function of aspartic proteases.
  • To elucidate the mechanism governing flap opening and substrate binding pocket accessibility.

Main Methods:

  • Molecular dynamics (MD) and metadynamics simulations were performed on apo Plm-II and BACE-1.
  • Side-chain torsion angles (χ1 and χ2 of tyrosine) were used as collective variables to sample flap transitions.
  • The impact of tyrosine mutation to alanine was simulated to assess its effect on flap flexibility.

Main Results:

  • Metadynamics simulations successfully sampled the transition between normal and flipped tyrosine states, which were equally populated.
  • H-bond interactions stabilize the normal (tryptophan) and flipped (catalytic aspartate) states.
  • Tyrosine mutation to alanine resulted in reduced flap flexibility and flap collapse, mirroring experimental observations.

Conclusions:

  • Tyrosine side-chain ring flipping is the key determinant of flap dynamics in aspartic proteases.
  • This dynamic behavior regulates the opening and closing of the substrate binding pocket.
  • Flap flexibility is essential for the catalytic activity of these enzymes.