Correlations between secondary structure- and protein-protein interface-mimicry: the interface mimicry hypothesis

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Small molecules, termed "minimalist mimics," are designed to disrupt protein-protein interactions (PPIs).
• These designs often rely on the Secondary Structure Hypothesis, assuming mimics mimicking secondary structures at interfaces can perturb PPIs.

Purpose of the Study:

• To rigorously test the Secondary Structure Hypothesis by analyzing small molecule-protein complex structures.
• To investigate the relationship between preferred small molecule conformations and secondary structures at PPI interfaces.
• To propose and support a complementary hypothesis based on observed data.

Main Methods:

• Simulating preferred conformations of novel minimalist mimics.
• Systematically overlaying these conformations onto a large dataset (>240,000) of crystallographically characterized PPI interfaces.
• Analyzing specific instances where mimics overlaid well on PPI interfaces to identify relevant secondary structures.

Main Results:

• Identified chemotypes that frequently overlay with side chains on various PPI interfaces.
• Determined that good secondary structure mimics do not necessarily overlay frequently on PPI interfaces.
• Found that preferred conformer overlays on PPI interfaces do not consistently involve secondary structures.

Conclusions:

• The Secondary Structure Hypothesis lacks direct empirical support from existing structural data.
• The study introduces and supports the Interface Mimicry Hypothesis, which is complementary and data-abundant.
• The Interface Mimicry Hypothesis provides a new framework for designing small molecules targeting PPIs.