Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention

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.