M. Neri, M. Cascella and C. Micheletti
Influence of conformational fluctuations on enzymatic
activity: modelling the functional motion of beta-secretase
J. Phys. Condens. Matter 17 S1581-S1593 (2005)
Preprint full text (cond-mat archive).
Link to online article.
Considerable insight into the functional activity of proteins and
enzymes can be obtained by studying the low-energy conformational
distortions that the biopolymer can sustain. We carry out the
characterization of these large scale structural changes for a protein
of considerable pharmaceutical interest, the human $\beta$-secretase.
Starting from the crystallographic structure of the protein, we use
the recently introduced \beta-Gaussian model to identify, with
negligible computational expenditure, the most significant distortion
occurring in thermal equilibrium and the associated time scales. The
application of this strategy allows to gain considerable insight into
the putative functional movements and, furthermore, helps to identify
a handful of key regions in the protein which have an important
mechanical influence on the enzymatic activity despite being spatially
distant from the active site. The results obtained within the Gaussian
model are validated through an extensive comparison against an
all-atom Molecular Dynamics simulation.