Biomedical subjects

Daniel L Cox

Publications and source records attributed to Daniel L Cox.

6 recordsLinked to original sources

PubMed2006

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 beta-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.

Animals↗

PubMed2006

Prion disease: exponential growth requires membrane binding.

A hallmark feature of prions, whether in mammals or yeast and fungi, is exponential growth associated with fission or autocatalysis of protein aggregates. We have employed a rigorous kinetic analysis to recent data from transgenic mice lacking a glycosylphosphatidylinositol membrane anchor to the normal cellular PrP(C) protein, which show that toxicity requires the membrane binding. We find as well that the membrane is necessary for exponential growth of prion aggregates; without it, the kinetics is simply the quadratic-in-time growth characteristic of linear elongation as observed frequently in in vitro amyloid growth experiments with other proteins. This requires both: i), a substantial intercellular concentration of anchorless PrP(C), and ii), a concentration of small scrapies seeding aggregates from the inoculum, which remains relatively constant with time and exceeds the concentration of large polymeric aggregates. We also can explain via this analysis why mice heterozygous for the anchor-full/anchor-free PrP(C) proteins have more rapid incubation than mice heterozygous for anchor-full/null PrP(C), and contrast the mammalian membrane associated fission or autocatalysis with the membrane free fission of yeast and fungal prions.

Animals↗

PubMed2005

Structure of infectious prions: stabilization by domain swapping.

A candidate structure for the minimal prion infectious unit is a recently discovered protein oligomer modeled as a beta-helical prion trimer (BPT); BPTs can stack to form cross-beta fibrils and may provide insight into protein aggregates of other amyloid diseases. However, the BPT lacks a clear intermonomer binding mechanism. Here we propose an alternative domain-swapped trimeric prion (DSTP) model and show with molecular dynamics (MD) that the DSTP has more favorable intermonomer hydrogen bonding and proline dihedral strain energy than the BPT. This new structural proposal may be tested by lysine and N terminus fluorescent resonance energy transfer (FRET) either directly on recombinant prion protein amyloid aggregates or on synthetic constructs that contain the proline/lysine-rich hinge region critical for domains to swap. In addition, the domain swapping may provide 1) intrinsic entanglement, which can contribute to the remarkable temperature stability of the infectious prion structure and help explain the absence of PrP(Sc) monomers, 2) insight into why specific prolines are potentially relevant to three inherited forms of prion disease, and 3) a simple explanation of prion strains assuming the strain is encoded in the monomer number of the oligomers.

Amyloid↗

PubMed2004

Lateral organization of cholesterol molecules in lipid-cholesterol assemblies.

We present results of an off-lattice simulation of a two-component planar system, as a model for lateral organization of cholesterol molecules in lipid-cholesterol assemblies. We explore the existence of "superlattice" structures even in fluid systems, in the absence of an underlying translational long-range order, and study their coupling to hexatic or bond-orientational order. We discuss our results in context of geometric superlattice theories and "condensation complexes" in understanding a variety of experiments in artificial lipid-cholesterol assemblies.

Biophysics↗

PubMed2004

Modeling amyloid beta-peptide insertion into lipid bilayers.

Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (Abeta) 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 Abeta 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 Abeta42, because of the extra hydrophobic residues relative to Abeta40, is more likely to adopt this conformation than Abeta40 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 Abeta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of Abeta mutants. These can be used through further experiments to test our hypothesis.

Algorithms↗

PubMed2003

Simulations of oligomeric intermediates in prion diseases.

We extend our previous stochastic cellular automata-based model for two-dimensional (areal) aggregation of prion proteins on neuronal surfaces. The new anisotropic model allows 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 noninfectious 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.

Algorithms↗