Nonnative interactions in coupled folding and binding processes of intrinsically disordered proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Proteins rely on molecular interactions for function, with both native and nonnative interactions playing crucial roles.
• Nonnative interactions can disrupt binding kinetics, while native interactions ensure complex stability and specificity.
• Intrinsically disordered proteins (IDPs) lack stable structures, making nonnative interactions potentially more influential in their binding dynamics due to high flexibility.

Purpose of the Study:

• To investigate the impact of nonnative hydrophobic interactions on the coupled folding and binding processes of IDPs.
• To explore the interplay between nonnative interactions, chain flexibility, and the binding kinetics of IDPs.

Main Methods:

• Utilized molecular dynamics simulations to model protein behavior.
• Analyzed free-energy profiles, binding rates, and thermodynamic/kinetic properties.
• Examined the influence of varying strengths of nonnative hydrophobic interactions.

Main Results:

• Introduction of nonnative hydrophobic interactions led to rugged free-energy profiles and the emergence of intermediate states.
• Binding rates initially increased then decreased significantly with increasing strength of nonnative hydrophobic interactions.
• Disordered systems exhibited greater susceptibility to nonnative interactions compared to ordered systems.

Conclusions:

• Nonnative hydrophobic interactions critically affect the folding and binding of IDPs, altering their kinetic and thermodynamic landscapes.
• The 'fly-casting' mechanism, a kinetic advantage of IDPs, is enhanced by nonnative hydrophobic interactions.
• Chain flexibility plays a key role in how IDPs respond to nonnative interactions, with implications for protein aggregation.