A thermodynamic investigation of amyloid precursor protein processing by human gamma-secretase

Human gamma-secretase cleaves the transmembrane domains (TMDs) of amyloid precursor protein (APP) into pathologically relevant amyloid-beta peptides (A beta s). The detailed mechanisms of the unique endoproteolytic cleavage by the presenilin 1 domain (PS1) of gamma-secretase are still poorly understood. Herein, we provide thermodynamic insights into how the alpha-helical APP TMD is processed by gamma-secretase and elucidate the specificity of A beta 48/A beta 49 cleavage using unbiased molecular dynamics and bias-exchange metadynamics simulations. The thermodynamic data show that the unwinding of APP TMD is driven by water hydration in the intracellular pocket of PS1, and the scissile bond T32-L33 or L33-V34 of the APP TMD can slide down and up to interact with D257/D385 to achieve endoproteolysis. In the wild-type system, the L33-V34 scissile bond is more easily hijacked by D257/D385 than T32-L33, resulting in higher A beta 49 cleavage, while the T32N mutation on the APP TMD decreases the energy barrier of the sliding of the scissile bonds and increases the hydrogen bond occupancy for A beta 48 cleavage. In summary, the thermodynamic analysis elucidates possible mechanisms of APP TMD processing by PS1, which might facilitate rational drug design targeting gamma-secretase. Thermodynamic analysis from unbiased molecular dynamics and bias-exchange metadynamics simulations reveals possible mechanisms on how gamma-secretase cleaves the transmembrane domains of amyloid precursor protein into amyloid-beta peptides.