Identifying weak interdomain interactions that stabilize the supertertiary structure of the N-terminal tandem PDZ domains of PSD-95

PDZ domain Tandem Energy landscape
DOI: 10.1038/s41467-018-06133-0 Publication Date: 2018-09-07T11:11:34Z
ABSTRACT
Abstract Previous studies of the N-terminal PDZ tandem from PSD-95 produced divergent models and failed to identify interdomain contacts stabilizing structure. We used ensemble single-molecule FRET along with replica-exchange molecular dynamics fully characterize energy landscape. Simulations experiments identified two conformations: an open-like conformation a small contact interface stabilized by salt bridges, closed-like larger surface-exposed hydrophobic residues. Both interfaces were confirmed experimentally. Proximity binding pockets may explain observed coupling between binding. The low-energy barrier conformations allows submillisecond dynamics, which time-averaged in previous NMR studies. Moreover, likely overridden lattice as crystal structures rarely sampled simulations. Our hybrid approach can transient interactions, are abundant multidomain proteins yet often obscured dynamic averaging.
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