Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.

Comparison on the WT and truncated substrates shows a clear trend of decreasing free energy differences between β3-associated (RC = 9–11 Å) and dissociated states (RC = 15–16 Å) in the order ΔΔG res,APP > ΔΔG res,Aβ53 > ΔΔG res,Aβ52 > ΔΔG res,Aβ51 , regardless of the chosen PS1 protonation state (Fig. 2b and Supplementary Fig.

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