Highly polar environments catalyze the unfolding of PrP C helix 1.

The first alpha-helix (H1) likely plays an important role in the conversion of the cellular prion protein (PrP(C)) into its pathogenic isoform (PrP(Sc)). In this conversion, H1 may either have to unfold or may represent a site of intermolecular contact. A recent molecular dynamics simulation suggested that H1 can unfold if it is detached from the protein core (Hirschberger et al. in Biophys J 90:3908, 2006). It has been hypothesized that the high dielectric constant epsilon (S) of the bulk water environment facilitates the unfolding of H1. To check this hypothesis, we performed a number of replica exchange molecular dynamics simulations of an H1 peptide in solvents of different epsilon (S). We found that the equilibrium helix fraction in water is less than 40%, in agreement with previous experimental findings, and that the helix unfolds much faster in water than in less polar solvents. The kinetically stabilizing effect of the organic solvents is largely unspecific and correlates well with their dielectric constant epsilon (S).

Simulated Solute Tempering.

For the enhanced conformational sampling in molecular dynamics (MD) simulations, we present "simulated solute tempering" (SST) which is an easy to implement variant of simulated tempering. SST extends conventional simulated tempering (CST) by key concepts of "replica exchange with solute tempering" (REST, Liu et al. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13749). We have applied SST, CST, and REST to molecular dynamics (MD) simulations of an alanine octapeptide in explicit water. The weight parameters required for CST and SST are determined by two different formulas whose performance is compared. For SST only one of them yields a uniform sampling of the temperature space. Compared to CST and REST, SST provides the highest exchange probabilities between neighboring rungs in the temperature ladder. Concomitantly, SST leads to the fastest diffusion of the simulation system through the temperature space, in particular, if the "even-odd" exchange scheme is employed in SST. As a result, SST exhibits the highest sampling speed of the investigated tempering methods.

How a frog can learn what is where in the dark.

During the night 180 lateral-line organs allow the clawed frog Xenopus to localize prey by detecting water waves emanating from insects floundering on the water surface. Not only can the frog localize prey but it can also determine its character. This suggests waveform reconstruction, and a key question is how the frog can establish the appropriate neuronal hardware. Detecting time differences arising from the input on the skin is a key to neuronal information processing, and spike-timing-dependent synaptic plasticity (STDP) therefore seems to be the natural tool. We show how supervised STDP allows a frog to learn what is where in the dark. Learning can also be derived from a minimization principle.