arXiv subjects

Daniel L. Cox

Publications and source records attributed to Daniel L. Cox.

13 recordsLinked to original sources

arXiv2021

Neurodegenerative damage reduces firing coherence in a continuous attractor model of grid cells

Grid cells in the dorsolateral band of the medial entorhinal cortex(dMEC) display strikingly regular periodic firing patterns on a lattice of positions in 2-D space. This helps animals to encode relative spatial location without reference to external cues. The dMEC is damaged in the early stages of Alzheimer's Disease, which affects navigation ability of a disease victim, reducing the synaptic density of neurons in the network. Within an established 2-dimensional continuous attractor neural network model of grid cell activity, we introduce damage parameterized by radius and by the strength of the synaptic output for neurons in the damaged region. The proportionality of the grid field flow on the dMEX to the velocity of the model organism is maintained, but when we examine the coherence of the grid cell firing field in the form of the Fourier transform (Bragg peaks) of the grid lattice, we find that a wide range of damage radius and strength induces an incoherent structure with only a single central peak, adjacent to narrow bands of striped (two additional peaks), which abut an orthorhombic pattern (four additional peaks), that abuts the undamaged hexagonal region (six additional peaks). Within the damaged region, grid cells show no Bragg peaks, and outside the damaged region the central Bragg peak strength is largely unaffected. There is a re-entrant region of normal grid firing for very large damage area. We anticipate that the modified grid cell behavior can be observed in non-invasive fMRI imaging of the dMEC.

q-bio.NC↗

arXiv2017

Molecular Dynamics-Based Strength Estimates of Beta-Solenoid Proteins

The use of beta-solenoid proteins as functionalizable, nanoscale, self-assembling molecular building blocks may have many applications, including templating the growth of wires or higher-dimensional structures. By understanding their mechanical strengths, we can efficiently design the proteins for specific functions. We present a study of the mechanical properties of seven beta-solenoid proteins using GROMACS molecular dynamics software to produce force/torque-displacement data, implement umbrella sampling of bending/twisting trajectories, produce Potentials of Mean Force (PMFs), extract effective spring constants, and calculate rigidities for two bending and two twisting directions for each protein. We examine the differences between computing the strength values from force/torque-displacement data alone and PMF data, and show how higher precision estimates can be obtained from the former. In addition to the analysis of the methods, we report estimates for the bend/twist persistence lengths for each protein, which range from 0.5-3.4 $μ$m. We note that beta-solenoid proteins with internal disulfide bridges do not enjoy enhanced bending or twisting strength, and that the strongest correlate with bend/twist rigidity is the number of hydrogen bonds per turn. In addition, we compute estimates of the Young's modulus ($Y$) for each protein, which range from $Y$ = 3.5 to 7.2 GPa.

q-bio.BM↗

arXiv2016

All-atom Molecular Dynamics Simulations of the Projection Domain of the Intrinsically Disordered htau40 Protein

We have performed all atom molecular dynamics simulations on the projection domain of the intrinsically disordered htau40 protein. After generating a suitable ensemble of starting conformations at high temperatures, at room temperature in an adaptive box algorithm we have generated histograms for the radius of gyration, secondary structure time series, generated model small angle x-ray scattering intensities, and model chemical shift plots for comparison to nuclear magnetic resonance data for solvated and filamentous tau. Significantly, we find that the chemical shift spectrum is more consistent with filamentous tau than full length solution based tau. We have also carried out principle component analysis and find three basics groups: compact globules, tadpoles, and extended hinging structures. To validate the adaptive box and our force field choice, we have run limited simulations in a large conventional box with varying force fields and find that our essential results are unchanged. We also performed two simulations with the TIP4P-D water model, the effects of which depended on whether the initial configuration was compact or extended.

q-bio.BM↗

arXiv2014

Simulated Cytoskeletal Collapse via Tau Degradation

We present a coarse-grained two dimensional mechanical model for the microtubule-tau bundles in neuronal axons in which we remove taus, as can happen in various neurodegenerative conditions such as Alzheimer's disease, tauopathies, and chronic traumatic encephalopathy. Our simplified model includes (i) taus modeled as entropic springs between microtubules, (ii) removal of taus from the bundles due to phosphorylation, and (iii) a possible depletion force between microtubules due to these dissociated phosphorylated taus. We equilibrate upon tau removal using steepest descent relaxation. In the absence of the depletion force, the transverse rigidity to radial compression of the bundle falls to zero at about 60% tau occupancy, in agreement with standard percolation theory results. However, with the attractive depletion force, spring removal leads to a first order collapse of the bundles over a wide range of tau occupancies for physiologically realizable conditions. While our simplest calculations assume a constant concentration of microtubule intercalants to mediate the depletion force, including a dependence that is linear in the detached taus yields the same collapse. Applying percolation theory to removal of taus at microtubule tips, which are likely to be the protective sites against dynamic instability, we argue that the microtubule instability can only obtain at low tau occupancy, from 0.06-0.30 depending upon the tau coordination at the microtubule tips. Hence, the collapse we discover is likely to be more robust over a wide range of tau occupancies than the dynamic instability. We suggest in vitro tests of our predicted collapse.

q-bio.NC↗

arXiv2010

Evaluating force field accuracy with long-time simulations of a tryptophan zipper peptide

We have combined a custom implementation of the fast multiple-time-stepping LN integrator with parallel tempering to explore folding properties of small peptides in implicit solvent on the time scale of microseconds. We applied this algorithm to the synthetic β-hairpin trpzip2 and one of its sequence variants W2W9. Each simulation consisted of over 12 μs of aggregated virtual time. Several measures of folding behavior showed convergence, allowing comparison with experimental equilibrium properties. Our simulations suggest that the electrostatic interaction of tryptophan sidechains is responsible for much of the stability of the native fold. We conclude that the ff99 force field combined with ff96 ϕ and ψ dihedral energies and implicit solvent can reproduce plausible folding behavior in both trpzip2 and W2W9.

q-bio.BM↗

arXiv2004

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.

physics.bio-ph↗

arXiv2003

Hysteresis loops of Co-Pt perpendicular magnetic multilayers

We develop a phenomenological model to study magnetic hysteresis in two samples designed as possible perpendicular recording media. A stochastic cellular automata model captures cooperative behavior in the nucleation of magnetic domains. We show how this simple model turns broad hysteresis loops into loops with sharp drops like those observed in these samples, and explains their unusual features. We also present, and experimentally verify, predictions of this model, and suggest how insights from this model may apply more generally.

cond-mat↗

arXiv2003

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.

physics.bio-ph↗

arXiv2000

Toward a systematic 1/d expansion: Two particle properties

We present a procedure to calculate 1/d corrections to the two-particle properties around the infinite dimensional dynamical mean field limit. Our method is based on a modified version of the scheme of Ref. onlinecite{SchillerIngersent}}. To test our method we study the Hubbard model at half filling within the fluctuation exchange approximation (FLEX), a selfconsistent generalization of iterative perturbation theory. Apart from the inherent unstabilities of FLEX, our method is stable and results in causal solutions. We find that 1/d corrections to the local approximation are relatively small in the Hubbard model.

cond-mat.str-el↗

arXiv1999

Crystal Field Triplets: A New Route to Non-Fermi Liquid Physics

A model for crystal field triplet ground states on rare earth or actinide ions with dipolar and quadrupolar couplings to conduction electrons is studied for the first time with renormalization group methods. The quadrupolar coupling leads to a new nontrivial, non-Fermi liquid fixed point, which survives in an intermediate valence Anderson model. The calculated magnetic susceptibility displays one parameter scaling, going as $T^{-α}$ ($α\approx 0.4$) at intermediate temperatures, reminiscent of the non-Fermi liquid alloy UCu_{5-x}Pd_x.

cond-mat.str-el↗

arXiv1999

Small Energy Scale for Mixed-Valent Uranium Materials

We investigate a two-channel Anderson impurity model with a $5f^1$ magnetic and a $5f^2$ quadrupolar ground doublet, and a $5f^2$ excited triplet. Using the numerical renormalization group method, we find a crossover to a non-Fermi liquid state below a temperature $T^*$ varying as the $5f^2$ triplet-doublet splitting to the 7/2 power. To within numerical accuracy, the non-linear magnetic susceptibility and the $5f^1$ contribution to the linear susceptibility are given by universal one-parameter scaling functions. These results may explain UBe$_{13}$ as mixed valent with a small crossover scale $T^*$.

cond-mat.str-el↗

arXiv1998

Mixed-valent regime of the two-channel Anderson impurity as a model for UBe_13

We investigate the mixed-valent regime of a two-configuration Anderson impurity model for uranium ions, with separate quadrupolar and magnetic doublets. With a new Monte Carlo approach and the non-crossing approximation we find: (i) A non-Fermi-liquid fixed point with two-channel Kondo model critical behavior; (ii) Distinct energy scales for screening the low-lying and excited doublets; (iii) A semi-quantitative explanation of magnetic-susceptibility data for U$_{1-x}$Th$_x$Be$_{13}$ assuming 60-70% quadrupolar doublet ground-state weight, supporting the quadrupolar-Kondo interpretation.

cond-mat.str-el↗

arXiv1993

Spin-Flavor Separation and Non-Fermi Liquid Behavior in the Multichannel Kondo Problem: A Large N Approach

We consider a $SU(N)\times SU(M)$ generalization of the multichannel single-impurity Kondo model which we solve analytically in the limit $N\rightarrow \infty$, $M\rightarrow\infty$, with $γ=M/N$ fixed. Non-Fermi liquid behavior of the single electron Green function and of the local spin and flavor susceptibilities occurs in both regimes, $N\le M$ and $N > M$, with leading critical exponents {\em identical} to those found in the conformal field theory solution for {\em all} $N$ and $M$ (with $M\ge 2$). We explain this remarkable agreement and connect it to ``spin-flavor separation", the essential feature of the non-Fermi-liquid fixed point of the multichannel Kondo problem.

cond-mat↗