Magnetic Correlations and Pairing in the 1/5-Depleted Square Lattice Hubbard Model

We study the single-orbital Hubbard model on the 1/5-depleted square-lattice geometry, which arises in such diverse systems as the spin-gap magnetic insulator CaV4O9 and ordered-vacancy iron selenides, presenting new issues regarding the origin of both magnetic ordering and superconductivity in these materials. We find a rich phase diagram that includes a plaquette singlet phase, a dimer singlet phase, a Néel and a block-spin antiferromagnetic phase, and stripe phases. Quantum Monte Carlo simulations show that the dominant pairing correlations at half filling change character from d wave in the plaquette phase to extended s wave upon transition to the Néel phase. These findings have intriguing connections to iron-based superconductors, and suggest that some physics of multiorbital systems can be captured by a single-orbital model at different dopings

Simulations of Oligomeric Intermediates in Prion Diseases

We extend our previous stochastic cellular automata based model for areal aggregation of prion proteins on neuronal surfaces. The new anisotropic model allow us to simulate both strong beta-sheet and weaker attachment bonds between proteins. Constraining binding directions allows us to generate aggregate structures with the hexagonal lattice symmetry found in recently observed in vitro experiments. We argue that these constraints on rules may correspond to underlying steric constraints on the aggregation process. We find that monomer dominated growth of the areal aggregate is too slow to account for some observed doubling time-to-incubation time ratios inferred from data, and so consider aggregation dominated by relatively stable but non-infectious oligomeric intermediates. We compare a kinetic theory analysis of oligomeric aggregation to spatially explicit simulations of the process. We find that with suitable rules for misfolding of oligomers, possibly due to water exclusion by the surrounding aggregate, the resulting oligomeric aggregation model maps onto our previous monomer aggregation model. Therefore it can produce some of the same attractive features for the description of prion incubation time data. We propose experiments to test the oligomeric aggregation model.Comment: 8 pages, 10 figures For larger versions of several figures, see http://asaph.ucdavis.edu/~dmobley and click on the prion paper lin

Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A beta) can insert into cell membranes and form harmful ion channels, we model insertion of the 40 and 42 residue forms of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease, and find that all but one of the mutants change the insertion behavior by causing the peptide to spend more simulation steps in only one leaflet of the bilayer. We also find that A-beta 42, because of the extra hydrophobic residues relative to A-beta 40, is more likely to adopt this conformation than A-beta 40 in both wild-type and mutant forms. We argue qualitatively why these effects happen. Here, we present our results and develop the hypothesis that this partial insertion increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of A-beta mutants. These can be used through further experiments to test our hypothesis.Comment: 14 pages; 8 figures; 2nd revisio

A Mechanism for Copper Inhibition of Infectious Prion Conversion

We employ ab initio electronic structure calculations to obtain two structural models for copper bound in the strongest binding site of the noninfectious form of the prion protein. The models are compatible with available experimental constraints from electron spin resonance data. The bending of the peptide backbone attendant with the copper binding is not compatible with the requisite straight β-strand backbone structure for the same sequence contained in two recently proposed models of the prion protein structure in its infectious form. We hypothesize that copper binding at this site is protective against conversion to the infectious form, discuss experimental data that appear to support and conflict with our hypothesis, and propose tests using recombinant prion protein, genetically modified cultured neurons, and transgenic mice

Theoretical Study of DNA Damage Recognition via Electron Transfer from the [4Fe-4S] Complex of MutY

The mechanism of site-specific recognition of DNA by proteins has been a long-standing issue. The DNA glycosylase MutY, for instance, must find the rare 8-oxoguanine-adenine mismatches among the large number of basepairs in the DNA. This protein has a [4Fe-4S] cluster, which is highly conserved in species as diverse as Escherichia Coli and Homo sapiens. The mixed-valent nature of this cluster suggests that charge transfer may play a role in MutY's function. We have studied the energetics of the charge transfer in Bacillus stearothermophilus MutY-DNA complex using multiscale calculation including density functional theory and molecular dynamics. The [4Fe-4S] cluster in MutY is found to undergo 2+ to 3+ oxidation when coupling to DNA through hole transfer, especially when MutY is near an oxoguanine modified base (oxoG). Employing the Marcus theory for electron transfer, we find near optimal Frank-Condon factors for electron transfer from MutY to oxoguanine modified base. MutY has modest selectivity for oxoguanine over guanine due to the difference in oxidation potential. The tunneling matrix element is significantly reduced with the mutation R149W, whereas the mutation L154F reduces the tunneling matrix element as well as the Frank-Condon factor. Both L154F and R149W mutations are known to dramatically reduce or eliminate repair efficiency. We suggest a scenario where the charge transfer leads to a stabilization of the specific binding conformation, which is likely the recognition mode, thus enabling it to find the damaged site efficiently