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

• DOI: 10.1038/s41467-018-06133-0
• Publication Date: 2018-09-07T11:11:34Z
• Authors: Inna S. Yanez Orozco; Frank A. Mindlin; Junyan Ma; Bo Wang; Brie Levesque; Matheu Spencer; Soheila Rezaei Ad...; George Hamilton; Feng Ding; Mark E. Bowen; Hugo Sanabria
• Keywords: PDZ domain; Tandem; Energy landscape

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.