Journal
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 13, Issue 6, Pages 5009-5016Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.2c00685
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Funding
- National Science Foundation of China [21977011]
- Shenzhen Fundamental Research Program [GXWD20201231165807007-20200827170132001]
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This study develops a multiscale approach to explore the pathways and kinetics of peptide aggregation nucleation. The research reveals a two-step mechanism for A beta(16-21) amyloid nucleation, and an unexpected atypical mechanism at submillimolar concentrations.
Atomic descriptions of peptide aggregation nucleation remain lacking due to the difficulty of exploring complex configurational spaces on long time scales. To elucidate this process, we develop a multiscale approach combining a metadynamics-based method with cluster statistical mechanics to derive concentration-dependent free energy surfaces of nucleation at near-atomic resolution. A kinetic transition network of nucleation is then constructed and employed to systematically explore nucleation pathways and kinetics through stochastic simulations. This approach is applied to describe A beta(16-21) amyloid nucleation, revealing a two-step mechanism involving disordered aggregates at millimolar concentration, and an unexpected mechanism at submillimolar concentrations that exhibits kinetics reminiscent of classical nucleation but atypical pathways involving growing clusters with structured cores wrapped by disordered surface. When this atypical mechanism is operative, critical nucleus size can be reflected by the nucleation reaction order. Collectively, our approach paves the way for a more quantitative and detailed understanding of peptide aggregation nucleation.
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