Osmolyte Induced Changes in Peptide Conformational Ensemble Correlate with Slower Amyloid Aggregation: A...

Area of Science:

• Biochemistry
• Computational Biology
• Materials Science

Background:

• Stabilizing osmolytes influence amyloid aggregation kinetics and fibril characteristics.
• Osmolytes are known to modify peptide conformational dynamics and the physical properties of amyloid fibrils.

Purpose of the Study:

• To investigate the molecular mechanisms by which the osmolyte sorbitol affects the initial aggregation steps of an amyloid-forming peptide.
• To compare the aggregation process in the presence of sorbitol versus pure water using molecular simulations.

Main Methods:

• Utilized an extended coarse-grained force field to simulate larger aggregate sizes and longer time scales.
• Optimized the force field to accurately model the solution thermodynamics of sorbitol, the peptide, and their interactions with water.
• Performed molecular dynamics simulations of peptide aggregation in the presence and absence of sorbitol.

Main Results:

• Simulations revealed differences in aggregation kinetics and structural parameters with sorbitol compared to water, aligning with experimental data.
• Sorbitol-induced kinetic changes were attributed to altered monomer conformations, affecting nucleation and fibril association rates.
• In the presence of sorbitol, more numerous, smaller aggregates formed, with a higher propensity for parallel interpeptide contacts.

Conclusions:

• Sorbitol modulates amyloid aggregation by altering peptide conformational dynamics at the molecular level.
• The study provides molecular insights into how osmolytes influence amyloid formation, offering potential strategies for controlling aggregation processes.
• Findings support the role of osmolytes in modifying the structural and kinetic landscape of amyloid self-assembly.