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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Protease inhibition by serine protease inhibitors (serpins) involves large conformational changes.
  • Complex formation triggers reactive center loop (RCL) cleavage and insertion into β-sheet A, trapping the protease.

Purpose of the Study:

  • To perform the first detailed accelerated molecular dynamics simulation of RCL insertion in alpha-1-antitrypsin (α₁AT).
  • To investigate the role of structural elements and mutations in serpin inhibition and stability.

Main Methods:

  • Accelerated molecular dynamics simulations of cleaved RCL insertion in α₁AT.
  • Analysis of internal water pathways and structural plasticity.
  • Generation and analysis of α₁AT mutants (K168E, E346K, K168E/E346K) for inhibitory activity, stability, and polymerization.

Main Results:

  • Simulations revealed internal water pathways facilitating RCL residue incorporation.
  • Observed plasticity in helix F (hF) and a novel chaperone role for hF and thFs3A in RCL insertion.
  • Transient electrostatic interactions modulate inhibitory activity.
  • The E346K mutation enhanced inhibitory activity but increased polymerization rates.

Conclusions:

  • The study elucidates the mechanism of RCL insertion in serpins, highlighting the roles of water, hF, and thFs3A.
  • Mutation E346K suggests a gatekeeping role for residue E346 in maintaining the metastable native state of α₁AT.
  • Findings provide insights into serpin function and potential therapeutic strategies.