Molecular Mechanisms Governing Peptide Nanodisc Assembly and Stability

Area of Science:

• Biophysics
• Materials Science
• Computational Chemistry

Background:

• Apolipoprotein A-I mimetic 4F peptides form nanodiscs with lipids.
• The assembly and stability mechanisms of these peptide nanodiscs are not fully understood.

Purpose of the Study:

• To elucidate the de novo formation pathway of 4F nanodiscs with DMPC using molecular dynamics simulations.
• To identify molecular determinants governing 4F nanodisc assembly and stability.
• To compare 4F nanodiscs with MSP nanodiscs regarding stability and function.

Main Methods:

• Coarse-grained molecular dynamics (CG-MD) simulations to model nanodisc formation.
• All-atom back-mapping to analyze nanodisc rim structure.
• Experimental validation of simulation findings, including thermal stability and amyloid inhibition.

Main Results:

• A multistep assembly pathway (nucleation, fusion, maturation) for 4F nanodiscs was revealed.
• Nanodisc rim structure is heterogeneous, stabilized by specific peptide-lipid and peptide-peptide interactions.
• Lipid composition (DMPC vs. DPPC) and temperature significantly impact nanodisc integrity and stability.
• 4F nanodiscs showed lower thermal resilience than MSP nanodiscs but effectively inhibited Aβ fibrillization.

Conclusions:

• CG-MD simulations are effective for studying nanodisc assembly mechanisms.
• A mechanistic framework and design principles for single-helix peptide nanodiscs were established.
• Peptide-rimmed discoidal architecture is sufficient for suppressing amyloid nucleation, regardless of the specific peptide scaffold.