A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Protein-protein interactions are crucial for cellular functions.
• Intrinsically disordered proteins (IDPs) and protein binding domains mediate many interactions.
• SH3 domains bind proline-rich disordered segments, playing roles in signaling and regulation.

Purpose of the Study:

• To characterize the binding pathway of intrinsically disordered proteins (IDPs) to SH3 domains.
• To investigate the role of encounter complexes in protein-protein interactions.
• To understand the dynamics of binding between the yeast Abp1p SH3 domain (AbpSH3) and the intrinsically disordered protein ArkA.

Main Methods:

• Molecular dynamics simulations were employed.
• The binding process between AbpSH3 and ArkA was simulated.
• Conformational changes and interactions during binding were analyzed.

Main Results:

• ArkA adopts a pre-structured N-terminal segment (segment 1) and a less structured C-terminal segment (segment 2) before binding.
• Binding initiates via a flexible encounter complex with transient hydrophobic and electrostatic contacts.
• The transition from encounter complex to the fully engaged state is the slow step, involving specific contacts and hydrophobic surface burial.

Conclusions:

• The binding pathway of IDPs to SH3 domains involves a critical encounter complex intermediate.
• Segment 2 of ArkA appears to stabilize the correct binding orientation.
• Encounter complexes and nonnative hydrophobic interactions are important for SH3 domain-IDP binding in general.