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Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention.

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Targeting intrinsically disordered proteins (IDPs) is challenging. This study shows that stabilizing specific protein structures (conformational selection) can override sequence specificity, aiding the development of IDP-targeting drugs.

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Drug Discovery

Background:

  • Intrinsically disordered proteins (IDPs) lack stable structures, posing challenges for drug development.
  • It remains unclear if drugs stabilize new conformations or target existing transient states in IDPs.

Purpose of the Study:

  • To investigate the binding mechanisms of molecules targeting islet amyloid polypeptide (IAPP), an IDP implicated in Type II Diabetes.
  • To differentiate between induced-fit and conformational selection models for IDP binders.

Main Methods:

  • Utilized molecular dynamics simulations to generate structured conformations of IAPP.
  • Employed umbrella sampling to calculate conformation-specific binding affinities.
  • Assessed the selectivity of known IAPP binders against distinct α-helix and β-sheet IAPP conformations.

Main Results:

  • A two-state IAPP model accurately predicted experimental binder selectivity.
  • Foldamer binders showed complex mechanisms not fully explained by conformational selection alone.
  • Foldamer binding was sensitive to IAPP sequence variations, unlike β-breaking peptides.

Conclusions:

  • Conformational selection plays a crucial role in stabilizing IDPs and can override sequence specificity.
  • Fixed IDP conformations can serve as viable targets for therapeutic development.
  • Understanding these mechanisms is key for designing effective IDP-targeting drugs.