Design Guidelines to Control Rippled β-Sheets versus Pleated β-Sheets in Mixed-Chirality Peptides

Area of Science:

• Biochemistry
• Computational Biology
• Materials Science

Background:

• Amino acid sequences are crucial for designing proteins, biomaterials, and drugs.
• Rippled beta-sheets, theorized in 1953, have limited experimental understanding.
• Gaps exist in knowledge regarding the formation and conditions of rippled beta-sheets.

Purpose of the Study:

• To investigate the relationship between amino acid sequences and rippled beta-sheet formation.
• To predict the energetics of different beta-sheet conformations using computational methods.
• To understand the stabilizing factors, particularly hydrogen bonds, in rippled beta-sheet structures.

Main Methods:

• Utilized molecular dynamics (MD) and density functional theory (DFT) simulations.
• Predicted energetics for six systems forming parallel or antiparallel rippled and pleated beta-sheets.
• Analyzed local structures and hydrogen bond networks for stabilization insights.

Main Results:

• The lowest energy predicted structure for each system matched the single experimentally observed rippled beta-sheet.
• Peptides consistently adopted motifs maximizing backbone hydrogen bonds.
• An achiral glycine-glycine bridge reduced steric hindrance between valine residues.
• Intramolecular hydrogen bonds stabilized cyclic peptides in anhydrous conditions.

Conclusions:

• Sequence dictates beta-sheet conformation, favoring maximum hydrogen bonding.
• Specific structural motifs and amino acid compositions influence stability.
• Findings offer guidelines for designing novel peptides with preferred structures.