Simulating protein unfolding under pressure with a coarse-grained model

We describe and test a coarse-grained molecular model for the simulation of the effects of pressure on the folding/unfolding transition of proteins. The model is a structure-based one, which takes into account the desolvation barrier for the formation of the native contacts. The pressure is taken into account in a qualitative, mean field approach, acting on the parameters describing the native stabilizing interactions. The model has been tested by simulating the thermodynamic and structural behavior of protein GB1 with a parallel tempering Monte Carlo algorithm. At low effective pressures, the model reproduces the standard two-state thermal transition between the native and denatured states. However, at large pressures a new state appears. Its structural characteristics have been analyzed, showing that it corresponds to a swollen version of the native structure. This swollen state is at equilibrium with the native state at low temperatures, but gradually transforms into the thermally denatured state as temperature is increased. Therefore, our model predicts a downhill transition between the swollen and the denatured states. The analysis of the model permits us to obtain a phase diagram for the pressure-temperature behavior of the simulated system, which is compatible with the known elliptical shape of this diagram for real proteins

Adolescent exposure to the Spice/K2 cannabinoid JWH-018 impairs sensorimotor gating and alters cortical perineuronal nets in a sex-dependent manner.

The consumption of synthetic cannabinoids during adolescence is reported to be a risk factor for the appearance of psychiatric disorders later in life. JWH-018 was identified as one of the primary psychoactive components present in Spice/K2 preparations. This study evaluated the short- and long-term consequences of exposure to JWH-018 during the adolescence in anxiety-like behavior, fear extinction, and sensorimotor gating in male and female mice. Alterations in anxiety varied depending on the time interval between treatment and behavioral analysis along with sex, while no changes were observed in the extinction of fear memory. A decrease in prepulse inhibition of the startle reflex was revealed in male, but not female, mice at short- and long-term. This behavioral disturbance was associated with a reduction in the number of perineuronal nets in the prelimbic and infralimbic regions of the prefrontal cortex in the short-term. Furthermore, adolescent exposure to JWH-018 induced an activation of microglia and astrocytes in the prefrontal cortex of male mice at both time intervals. A transitory decrease in the expression of GAD67 and CB2 cannabinoid receptors in the prefrontal cortex was also found in male mice exposed to JWH-018. These data reveal that the treatment with JWH-018 during the adolescence leads to long-lasting neurobiological changes related to psychotic-like symptoms, which were sex-dependent.post-print2490 K

Time Series Analysis Applied to EEG Shows Increased Global Connectivity during Motor Activation Detected in PD Patients Compared to Controls.

Background: Brain connectivity has shown to be a key characteristic in the study of both Parkinson’s Disease (PD) and the response of the patients to the dopaminergic medication. Time series analysis has been used here for the first time to study brain connectivity changes during motor activation in PD. Methods: A 64-channel EEG signal was registered during unilateral motor activation and resting-state in 6 non-demented PD patients before and after the administration of levodopa and in 6 matched healthy controls. Spectral entropy correlation, coherence, and interhemispheric divergence differences among PD patients and controls were analyzed under the assumption of stationarity of the time series. Results: During the motor activation test, PD patients showed an increased correlation coefficient (both hands p < 0.001) and a remarkable increase in coherence in all frequency range compared to the generalized reduction observed in controls (both hands p < 0.001). The Kullback–Leibler Divergence (KLD) of the Spectral Entropy between brain hemispheres was observed to increase in controls (right hand p = 0.01; left hand p = 0.015) and to decrease in PD patients (right hand p = 0.02; left hand p = 0.002) with motor activation. Conclusions: Our results suggest that the oscillatory activity of the different cortex areas within healthy brains is relatively independent of the rest. PD brains exhibit a stronger connectivity which grows during motor activation. The levodopa mitigates this anomalous performance.post-print2,22 M

Modelos simples para estudiar el efecto de la presión en el plegamiento de proteínas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Física I, leída el 09-05-2014Depto. de Química FísicaFac. de Ciencias QuímicasTRUEunpu