No abstract

Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene ( MAPT ) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau’s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306 VQIVYK 311 . We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone 306 VQIVYK 311 motif forms metastable compact structures with its upstream sequence that modulates aggregation propensity. We report that disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.

Protein structural integrity and flexibility are intimately tied to solvation. Here, we examine the effect that changes in bulk and local solvent properties have on protein structure and stability. We observe the change in solvation of an unfolding of the protein model, melittin, in the presence of a denaturant, trifluoroethanol. The peptide system displays a well defined transition in that the tetramer unfolds without disrupting the secondary or tertiary structure. In the absence of local structural perturbation, we are able to reveal exclusively the role of solvation dynamics in protein structure stabilization and the (un)folding pathway. A sudden retardation in solvent dynamics, which is coupled to the change in protein structure, is observed at a critical trifluoroethanol concentration. The large amplitude conformational changes are regulated by the local solvent hydrophobicity and bulk solvent viscosity.fluoresence spectroscopy ͉ preferential solvation ͉ protein folding ͉ ultrafast hydration

We have studied the structural, energetic, and electronic properties of crystalline cellulose I using first-principles density functional theory (DFT) with semiempirical dispersion corrections. The predicted crystal structures of both Iα and Iβ phases agree well with experiments and are greatly improved over those predicted by DFT within the local and semilocal density approximations. The cohesive energy is analyzed in terms of interchain and intersheet interactions, which are calculated to be of similar magnitude. Both hydrogen bonding and van der Waals (vdW) dispersion forces are found to be responsible for binding cellulose chains together. In particular, dispersion corrections prove to be indispensable in reproducing the equilibrium intersheet distance and binding strength; however, they do not improve the underestimated hydrogen bond length from DFT. The computed energy gaps of crystalline cellulose are 5.7 eV (Iα) and 5.4 eV (Iβ), whereas localized surface states appear within the gap for surfaces. The interaction of cellulose with water is studied by investigating the adsorption of a single water molecule on the hydrophobic Iβ(100) surface. The formation of hydrogen bond at the water/cellulose interface is shown to depend sensitively on the adsorption site for example above the equatorial hydroxyls or the CH moieties pointing out of the cellulose sheets. VdW dispersion interactions also contribute significantly to the adsorption energy.

The folding dynamics of proteins and polypeptides is a complex process involving different time and length scales. [1][2][3][4] Among the secondary structural elements the α-helix is the most commonly found configuration with its stability resulting from the unique hydrogen bonding; the C=O group of an amino acid at the position i forms a hydrogen bond with the N-H group of another amino acid located at the position i+4. The thermodynamic properties of the α-helix are understood in the context of the helix-coil transition, but the dynamics, being of many steps, have a whole range of time scales. The rates have been reported using a variety of experimental methods [for recent reviews see refs. 5-7] including absorption, NMR, Raman, infrared, and circular dichroism. The helix-coil transition was believed to occur on the microsecond timescale, and only recently, by means of fluorescence detection, were the rates measured to be as short as 300 ns, [8][9][10] prompting the association of the 300 ns results with "ultrafast" dynamics.[9] Theoretical models of helix-coil (polymer type) transitions and molecular dynamics (MD) simulations (see below) have also provided a range of time scales. For example, Schwarz,[11] using Zimm-Bragg nucleation and elongation parameters,[12] estimated the "relaxation time" to be 0.1 microsecond, whereas the time scale in MD simulations of folding (sub-ns to μs) depends on the length and sequence. In order to resolve the primary processes of folding, the dynamics have to be observed with the shortest time resolution possible.In this contribution, we report the ultrafast folding dynamics of the α-helix with time resolution three orders of magnitude shorter than previously reported with fluorescence detection. The in situ measured heating time (3.5 ps), with the ultrafast T-jump method, [13] is determined by the water relaxation time of the peptide in pure water, as described below. Earlier, a T-jump with time resolution of 70 ps was used to study proteins by heating through dye molecules in the solution. [14] Here, the heating is directly through the water vibrations on the 3.5 ps time scale. We studied the α-helical alanine-based pentapeptide, Ac-W-(A) 3 -H + -NH 2 (Wh5), in an acetate buffer at pH = 4.8. Other alanine-based peptides with