Abstract
Considerable insight into the functional activity of proteins and enzymes canbe obtained by studying the low energy conformational distortions that thebiopolymer can sustain. We carry out the characterization of these large scalestructural changes for a protein of considerable pharmaceutical interest, the humanβ-secretase. Starting from the crystallographic structure of the protein, we use the recently introducedβ-Gaussian model to identify, with negligible computational expenditure, the mostsignificant distortions occurring in thermal equilibrium and the associated timescales. Theapplication of this strategy helps us to gain considerable insight into the putativefunctional movements and, furthermore, allows us to identify a handful of key regions inthe protein which have an important mechanical influence on the enzymatic activitydespite being spatially distant from the active site. The results obtained within theGaussian model are validated through an extensive comparison against an all-atommolecular dynamics simulation.
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