Quantum chemical modelling of sequence encoded energetics and electrostatic landscapes governing early peptide association in α- synuclein and amyloid β
Abstract
Abstract Context Early molecular association of α-synuclein and amyloid β (Aβ) underlies the formation of higher order assemblies implicated in Parkinson’s and Alzheimer’s diseases, yet how residue order shapes the molecular properties governing these initial association events remains poorly resolved. Here, aggregation prone peptide segments were compared with composition matched scrambled controls to isolate the contribution of sequence arrangement while conserving amino acid composition. Residue rearrangement produced distinct energetic responses in the two peptide systems. Aggregation prone Aβ exhibited an association energy of 115.617 kJ/mol compared with 232.552 kJ/mol for its control, whereas aggregation prone α-synuclein exhibited − 172.819 kJ/mol compared with − 494.371 kJ/mol for its control. These energetic differences were accompanied by contrasting intermolecular organization: aggregation prone α-synuclein formed 166 heavy atom contacts compared with 105 for its control, whereas aggregation prone Aβ formed 40 compared with 81. Residue rearrangement further reorganized molecular electrostatic potential (ESP) landscapes and Hirshfeld atomic charge distributions, while sequence descriptors revealed peptide specific changes in charge patterning, hydrophobic organization and molecular compactness. Together, these results established residue order as a determinant of early peptide association and revealed that identical amino acid compositions can generate distinct…
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