In-silico investigation of the molecular disruption of Aβ42 protofibril by stilbenoids

Amyloid-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math> aggregation into protofibrillar and fibrillar assemblies is a central hallmark of Alzheimer's disease (AD), making disruption of A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math>42 protofibrils a promising therapeutic strategy. Here, we assessed the destabilization potential of five naturally occurring biphenolic stilbenoids - Resveratrol, Piceid, Astringin, Piceatannol, and Rhapontigenin - through an integrated in silico approach. Molecular docking, 500 ns all-atom molecular dynamics simulations, MM-PBSA binding free energy calculations, and structural analyses (RMSD, RMSF, radius of gyration, hydrogen-bond and salt-bridge dynamics, intersheet contacts, and principal component analysis) were employed to capture ligand-induced perturbations in fibril stability. Docking revealed preferential binding at <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math>-sheet-forming hotspots (PHE19, PHE20, VAL36, GLY38) along the interchain interface. Among the studied compound, Rhapontigenin exhibited the most favorable binding free energy (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>Δ</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:mtext>bfe</mml:mtext></mml:mrow></mml:msub></mml:mrow></mml:mrow></mml:math> = <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>-</mml:mo><mml:mn>16.732</mml:mn><mml:mo>±</mml:mo><mml:mn>5.807</mml:mn></mml:mrow></mml:math> kcal/mol) and induced pronounced disruption of hydrogen-bond networks, salt-bridge integrity, and fibrillar compactness. Structural descriptors further indicated chain-terminal deformation, elevated RMSD and Rg, and broadened conformational sampling, reflecting loss of fibril rigidity. Piceatannol and Piceid exerted moderate destabilization effects, whereas Astringin and Resveratrol showed minimal impact. These findings identify Rhapontigenin as a potent destabilizer of A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math>42 protofibrils and highlight naturally derived stilbenoids as promising scaffolds for anti-amyloid drug design, while underscoring the value of simulation-driven strategies for targeting protein aggregates.