Protein core packing by dynamic combinatorial chemistry

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Dynamic combinatorial libraries (DCLs) offer a powerful platform for discovering novel molecular architectures.
• Understanding the principles governing the stability of self-assembled macromolecules is crucial for protein design.

Purpose of the Study:

• To demonstrate recursive selection of biologically relevant macromolecules from a DCL.
• To investigate the structural determinants of stability in peptide trimers.

Main Methods:

• Construction of a 36-peptide library capable of forming 8436 unique trimers.
• Systematic variation of hydrophobic residues (glycine, alanine, valine, leucine, isoleucine, phenylalanine) at six core positions.
• Analysis of trimer stability based on hydrophobic core packing.

Main Results:

• Identified that <0.2% of all possible core packing arrangements exhibit high folding stability.
• Demonstrated that stability is driven by intimate "jigsaw" packing rather than maximal hydrophobic surface area sequestration.
• Uncovered a nuanced rule for stable core packing, influenced by specific amino acid sequence combinations.

Conclusions:

• Recursive selection from DCLs is feasible for identifying stable macromolecular structures.
• Hydrophobic core packing geometry, specifically "jigsaw" fit, is a key determinant of peptide stability.
• A complex, sequence-dependent rule governs the formation of stable hydrophobic cores in peptides.