Decoding Solubility Signatures from Amyloid Monomer Energy Landscapes

This study investigates the energy landscapes of amyloid monomers, which are crucial for understanding protein misfolding mechanisms in Alzheimer's disease. While proteins possess inherent thermodynamic stability, environmental factors can induce deviations from native folding pathways, leading to misfolding and aggregation, phenomena closely linked to solubility. Using the UNOPTIM program, which integrates the UNRES potential into the Cambridge energy landscape framework, we conducted single-ended transition state searches and employed discrete path sampling to compute kinetic transition networks starting from PDB structures. These kinetic transition networks consist of local energy minima and the transition states that connect them, which quantify the energy landscapes of the amyloid monomers. We defined clusters within each landscape using energy thresholds and selected their lowest-energy structures for the structural analysis. Applying graph convolutional networks, we identified solubility trends and correlated them with structural features. Our findings identify specific minima with low solubility, characteristic of aggregation-prone states, highlighting the key residues that drive reduced solubility. Notably, the exposure of the hydrophobic residue Phe19 to the solvent triggers a structural collapse by disrupting the neighboring helix. Additionally, we investigated selected minima to determine the first passage times between states, thereby elucidating the kinetics of these energy landscapes. This comprehensive approach provides valuable insights into the thermodynamics and kinetics of Aβ monomers. By integration of multiple analytical techniques to explore the energy landscapes, our study investigates structural features associated with reduced solubility. These insights have the potential to inform future therapeutic strategies aimed at addressing protein misfolding and aggregation in neurodegenerative diseases.