Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent

Area of Science:

• Biophysics
• Computational Biology
• Protein Aggregation

Background:

• Amyloid-beta (Abeta) and beta2-microglobulin (beta2m) protein aggregation are linked to diseases like Alzheimer's and dialysis-related amyloidosis.
• Short peptides can also form amyloid fibrils in vitro, following a nucleation-polymerization process.
• Understanding the aggregation dynamics of these peptides is crucial for disease research.

Purpose of the Study:

• To investigate the thermodynamics and dynamics of octamerization for two amyloidogenic peptides: beta2m83-89 and Abeta16-22.
• To compare the aggregation properties of these peptides using molecular dynamics simulations.
• To elucidate the impact of hydrophobic character on peptide aggregation.

Main Methods:

• Employed long molecular dynamics (MD) simulations using the OPEP coarse-grained force field.
• Simulated the octamerization of beta2m83-89 (NHVTLSQ) and Abeta16-22 (KLVFFAE) peptides at 310 K.
• Analyzed multiple trajectories totaling 2.2 microseconds for beta2m83-89 and 4.8 microseconds for Abeta16-22, starting from random configurations.

Main Results:

• Found that both peptides share common aggregation properties but also exhibit significant differences.
• Observed that increased hydrophobicity, as in Abeta16-22 compared to beta2m83-89, reduces the population of bilayer beta-sheet assemblies.
• Demonstrated that higher hydrophobicity slows beta-sheet formation dynamics by increasing the average lifetime of configurations and simplifying the transition probability matrix.

Conclusions:

• Hydrophobic character significantly influences the aggregation thermodynamics and dynamics of amyloidogenic peptides.
• The findings provide insights into the distinct aggregation behaviors of Abeta and beta2m peptides.
• This study contributes to understanding the molecular mechanisms underlying amyloid-related diseases.