Assembly dynamics of two-beta sheets revealed by molecular dynamics simulations

Area of Science:

• Biophysics
• Computational Biology
• Materials Science

Background:

• Amyloidogenic peptides, like the human Islet amyloid polypeptide (IAPP) segment 20-29, are implicated in diseases.
• Understanding the early stages of protein aggregation, specifically beta sheet assembly, is crucial for disease mechanism elucidation.
• The polymorphic nature of amyloid aggregation suggests diverse assembly pathways.

Purpose of the Study:

• To investigate the assembly dynamics of antiparallel beta sheets formed by the IAPP 20-29 peptide.
• To explore how initial separation distances influence beta sheet assembly.
• To elucidate the mechanisms and driving forces behind early-stage fibril elongation.

Main Methods:

• All-atom molecular dynamics (MD) simulations with explicit water solvent.
• Simulations of two beta sheets with varying initial separation distances.
• Poisson-Boltzmann free energy analysis and quasiharmonic configuration entropy estimation.

Main Results:

• Beta sheet assembly observed in both lateral and longitudinal directions.
• Longitudinal assembly is significantly influenced by entropic contributions.
• A cyclic oligomeric state was identified as a potential intermediate in the aggregation pathway.

Conclusions:

• The study provides novel insights into the early-stage assembly pathway of IAPP peptides, highlighting bidirectional growth.
• Entropy plays a critical role in the longitudinal assembly of beta sheets.
• The findings suggest that the aggregation of IAPP is polymorphic, with cyclic structures being a possible oligomeric state.