Polymorphism of fibrillar structures depending on the size of assembled A beta(17-42) peptides

The size of assembled Aβ17-42 peptides can determine polymorphism during oligomerization and fibrillization, but the mechanism of this effect is unknown. Starting from separate random monomers, various fibrillar oligomers with distinct structural characteristics were identified using discontinuous molecular dynamics simulations based on a coarse-grained protein model. From the structures observed in the simulations, two characteristic oligomer sizes emerged, trimer and paranuclei, which generated distinct structural patterns during fibrillization. A majority of the simulations for trimers and tetramers formed non-fibrillar oligomers, which primarily progress to off-pathway oligomers. Pentamers and hexamers were significantly converted into U-shape fibrillar structures, meaning that these oligomers, called paranuclei, might be potent on-pathway intermediates in fibril formation. Fibrillar oligomers larger than hexamers generated substantial polymorphism in which hybrid structures were readily formed and homogeneous fibrillar structures appeared infrequently. © 2016 The Author(s).1

Enhancement of superconductive critical temperatures in almost empty or full bands in two dimensions: possible relevance to beta-HfNCl, C60 and MgB2

We examine possibility of enhancement of superconductive critical temperature in two-dimensions. The weak coupling BCS theory is applied, especially when the Fermi level is near the edges of the electronic bands. The attractive interaction depends on ${\bf k}$ due to screening. The density of states(DOS) does not have a peak near the bottom of the band, but $k$-dependent contribution to DOS (electron density on the Fermi surface) has a diverging peak at the bottom or top. These features lead to significant enhancement of the critical temperatures. The results are qualitatively consistent with the superconductive behaviors of HfNCl (\Tc \le 25K) and ZrNCl(\Tc \le 15K), C$_{60}$ with a field-effect transistor configuration (\Tc = 52K), and MgB$_2$ (\Tc \approx 40K) which have the unexpectedly high superconductive critical transition temperatures.Comment: 5 pages,4 figure

Localization Length Exponent in Quantum Percolation

Connecting perfect one-dimensional leads to sites i and j on the quantum percolation (QP) model, we calculate the transmission coefficient Tij(E) at an energy E near the band center and the averages of ΣijTij, Σijr2ijTij, and Σijr4ijTij to tenth order in the concentration p. In three dimensions, all three series diverge at pq=0.36+0.01−0.02, with exponents γ=0.82+0.10−0.15, γ+2ν, and γ+4ν. We find ν=0.38±0.07, differing from “usual” Anderson localization and violating the bound ν≥2/d of Chayes et al. [Phys. Rev. Lett. 57, 2999 (1986)]. Thus, QP belongs to a new universality class

Structural insight into conformational change in prion protein by breakage of electrostatic network around H187 due to its protonation

A conformational change from normal prion protein(PrPC) to abnormal prion protein(PrPSC) induces fatal neurodegenerative diseases. Acidic pH is well-known factors involved in the conformational change. Because the protonation of H187 is strongly linked to the change in PrP stability, we examined the charged residues R156, E196, and D202 around H187. Interestingly, there have been reports on pathological mutants, such as H187R, E196A, and D202N. In this study, we focused on how an acidic pH and pathological mutants disrupt this electrostatic network and how this broken network destabilizes PrP structure. To do so, we performed a temperature-based replica-exchange molecular dynamics (T-REMD) simulation using a cumulative 252 μs simulation time. We measured the distance between amino acids comprising four salt bridges (R156–E196/D202 and H187–E196/D202). Our results showed that the spatial configuration of the electrostatic network was significantly altered by an acidic pH and mutations. The structural alteration in the electrostatic network increased the RMSF value around the first helix (H1). Thus, the structural stability of H1, which is anchored to the H2–H3 bundle, was decreased. It induces separation of R156 from the electrostatic network. Analysis of the anchoring energy also shows that two salt-bridges (R156-E196/D202) are critical for PrP stability. © 2019, The Author(s).1

Atomic insights into the effects of pathological mutants through the disruption of hydrophobic core in the prion protein

Destabilization of prion protein induces a conformational change from normal prion protein (PrPC) to abnormal prion protein (PrPSC). Hydrophobic interaction is the main driving force for protein folding, and critically affects the stability and solvability. To examine the importance of the hydrophobic core in the PrP, we chose six amino acids (V176, V180, T183, V210, I215, and Y218) that make up the hydrophobic core at the middle of the H2-H3 bundle. A few pathological mutants of these amino acids have been reported, such as V176G, V180I, T183A, V210I, I215V, and Y218N. We focused on how these pathologic mutations affect the hydrophobic core and thermostability of PrP. For this, we ran a temperature-based replica-exchange molecular dynamics (T-REMD) simulation, with a cumulative simulation time of 28 μs, for extensive ensemble sampling. From the T-REMD ensemble, we calculated the protein folding free energy difference between wild-type and mutant PrP using the thermodynamic integration (TI) method. Our results showed that pathological mutants V176G, T183A, I215V, and Y218N decrease the PrP stability. At the atomic level, we examined the change in pair-wise hydrophobic interactions from valine-valine to valine-isoleucine (and vice versa), which is induced by mutation V180I, V210I (I215V) at the 180th–210th (176th–215th) pair. Finally, we investigated the importance of the π-stacking between Y218 and F175. © 2019, The Author(s).1

Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies

Gephyrin is critical for the structure, function, and plasticity of inhibitory synapses. Gephyrin mutations have been linked to various neurological disorders; however, systematic analyses of the functional consequences of these mutations are lacking. Here, we performed molecular dynamics simulations of gephyrin to predict how six reported point mutations might change the structural stability and/or function of gephyrin. Additional in silico analyses revealed that the A91T and G375D mutations reduce the binding free energy of gephyrin oligomer formation. Gephyrin A91T and G375D displayed altered clustering patterns in COS-7 cells and nullified the inhibitory synapse-promoting effect of gephyrin in cultured neurons. However, only the G375D mutation reduced gephyrin interaction with GABAA receptors and neuroligin-2 in mouse brain; it also failed to normalize deficits in GABAergic synapse maintenance and neuronal hyperactivity observed in hippocampal dentate gyrus-specific gephyrin-deficient mice. Our results provide insights into biochemical, cell-biological, and network-activity effects of the pathogenic G375D mutation. © 2021 The Author(s)1