Evaluating minimalist mimics by exploring key orientations on secondary structures (EKOS)

Area of Science:

• Computational chemistry and structural biology.
• Design and application of peptide mimics.

Background:

• Minimalist mimics display amino acid side-chains on non-polyamide scaffolds, offering potential for mimicking protein secondary structures like alpha-helices.
• Lack of standardized protocols hinders the selection and evaluation of minimalist mimics for specific applications, particularly in mimicking secondary structure side-chain orientations.

Purpose of the Study:

• To develop and validate a computational protocol for calibrating minimalist mimics against ideal secondary structures.
• To assess the conformational preferences and side-chain positioning of existing minimalist helical mimics.
• To evaluate the potential of these mimics in disrupting protein-protein interactions (PPIs).

Main Methods:

• Utilized quenched molecular dynamics (QMD) to generate an ensemble of low-energy conformers for minimalist mimics.
• Represented conformers and ideal secondary structure side-chain triads using Cα and Cβ coordinates.
• Developed the Exploring Key Orientations on Secondary structures (EKOS) protocol to overlay mimic conformers onto secondary structure side-chain triads, quantifying fit using root mean squared deviation (RMSD).

Main Results:

• The EKOS protocol successfully quantified the conformational bias of scaffolds towards different secondary structures and identified specific side-chain correspondences (e.g., i, i+4, i+7).
• Analysis revealed that several widely used minimalist α-helical mimics exhibit conformational preferences for non-helical structures and possess unexpected side-chain alignments in helical conformations.
• Simulations demonstrated the ability to match mimic conformations to actual protein/peptide structures at PPI interfaces, providing quantitative fit comparisons.

Conclusions:

• The EKOS protocol provides a robust method for evaluating minimalist mimics, revealing their conformational versatility and potential for broader applications than previously assumed.
• The findings suggest that minimalist mimics may have significant potential for disrupting PPI interfaces due to their conformational flexibility and varied side-chain orientations.
• This work facilitates the rational design and selection of minimalist mimics for specific therapeutic or research applications targeting protein-protein interactions.