Multistate B- to A- transition in protein-DNA Binding - How well is it described by current AMBER force fields?

When DNA interacts with a protein, its structure often undergoes a significant conformational adaptation, usually involving a transition from B-DNA towards the A-DNA form. This is not a two-state, but rather a multistate transition. The A- and B- forms differ mainly in sugar pucker (north/south) and glycosidic torsion χ (anti/high-anti). The combination of A-like pucker and B-like χ (and vice versa) represents the nature of the intermediate states between the pure A- and B- forms. Here we study how the A/B equilibrium and the A/B intermediate states at protein-DNA interfaces are modeled by current AMBER force fields. Eight diverse protein-DNA complexes and their naked (unbound) DNAs were simulated with OL15 and bsc1 force fields and an experimental combination OL15χOL3. We found that while the geometries of the A-like intermediate states agree well with the native X-ray geometries, their populations (stabilities) are significantly underestimated. Different force fields predict different propensities for A-like states growing in the order OL15 < bsc1 < OL15χOL3, yet all underestimate A-like form populations. Interestingly, the force fields seem to predict the correct sequence-dependent A-form propensity, as they predict larger populations of the A-like form in unbound DNA in those steps that acquire A-like conformations in protein-DNA complexes. The instability of A-like geometries in current force fields significantly alters the geometry of simulated protein-DNA complexes and destabilizes the binding motif, suggesting that refinement is required to improve description of protein-DNA interactions in AMBER force fields.Communicated by Ramaswamy H. Sarma.

All-night spectral and microstate EEG analysis in patients with recurrent isolated sleep paralysis.

The pathophysiology of recurrent isolated sleep paralysis (RISP) has yet to be fully clarified. Very little research has been performed on electroencephalographic (EEG) signatures outside RISP episodes. This study aimed to investigate whether sleep is disturbed even without the occurrence of a RISP episode and in a stage different than conventional REM sleep. 17 RISP patients and 17 control subjects underwent two consecutive full-night video-polysomnography recordings. Spectral analysis was performed on all sleep stages in the delta, theta, and alpha band. EEG microstate (MS) analysis was performed on the NREM 3 phase due to the overall high correlation of subject template maps with canonical templates. Spectral analysis showed a significantly higher power of theta band activity in REM and NREM 2 sleep stages in RISP patients. The observed rise was also apparent in other sleep stages. Conversely, alpha power showed a downward trend in RISP patients' deep sleep. MS maps similar to canonical topographies were obtained indicating the preservation of prototypical EEG generators in RISP patients. RISP patients showed significant differences in the temporal dynamics of MS, expressed by different transitions between MS C and D and between MS A and B. Both spectral analysis and MS characteristics showed abnormalities in the sleep of non-episodic RISP subjects. Our findings suggest that in order to understand the neurobiological background of RISP, there is a need to extend the analyzes beyond REM-related processes and highlight the value of EEG microstate dynamics as promising functional biomarkers of RISP.