Commentaries and original research on prion molecular biology from the webmaster. This is the directory to rather long individual articles with large graphics and animations. These articles are subject to frequent revision; reader comment is welcomed.

** Main Research Directory Projects may be viewed either by topic or in reverse chronology. The number of articles has gotten quite large, spanning nearly every possible topic in gene annotation and genomics from regulation of prion and doppel gene expression to quaternary structure of the resultant proteins. Typically, results from experimental articles are integrated and combined with output of molecular biology online tools to add value. Posted 20 Jan 99; index revised quarterly

**What Species Barrier? It is clear that the molecular basis for both species barriers and strain types have to do with prion quaternary structures and interacations. Here, the notion of species barrier is compentized and replaced by the more neutral idea of species transmission coefficient (STC). Existing data cannot be explained by phylogenetic disatance, natural selection, experimental bias. Quasi homo-oligomer interactions are suggested as a more probable mechanism, with dimer docking destabilized by various tertiary structure perturbations of an altered monomer. Posted 15 April 1997; revised 26 May 97

** Chicken prion: The prion sequence from chickens presents some anomalies. Indeed, highly inbreed, long-domesticated chickens may inadvertently harbor a TSE-causing mutation of the prion gene. It is aligned here by clamping techniques to marsupial and Jurassic placental mammal, in so far as possible: the chicken gene may only be paralogous to mammalian prion. The hexapeptide repeat region seems to have originated from a short palindrome, with a different but nearby nucleotides than mammalian octapeptide being amplified. Chicken structural domains are compared to the variations found in 34 mammalian species. Three tables. Posted 24 Dec 96; revised 3 Jan 97.

** Nearly-neutral mutations from primates:The principle of kinship polymorphisms is applied to human prion protein to predict six neutral polymorphisms. Hot spots for prion mutations (including the octapeptide repeat region) have different structural origins and different disease induction mechanisms. Identical mutations turn up repeatedly in unrelated human families, even though the genetic map is far from saturated.

Cumulative variation in 52 species along the prion protein is displayed and quantitated, identifying phylogenetic hot spots, invariant residues, and optimal fuzzy BLAST homology probes. Plain-text files are given for all known prion gene and protein sequences, published and unpublished. A database of gapped and aligned placental mammal sequences is provided along with a universal residue numbering scheme.

Sporadic CJD is diminishing as cases once said to be non-familial are yielding to improved DGGE gel methods, sequencing of the promoter region, more extensive interviewing of families, and parallels to ALS. Two tables and color graphic. Posted 23 Dec 96; revised 9 Feb 97.

** Prion evolution: Prion protein is unusually conserved evolutionarily -- mutational rates are estimated. The prion gene can be deleted with non-catastrophic impact, yet the sequence is more strongly conserved than hemoglobin. Selective pressure can be componentized between nucleic acid and protein by examing silent codon change.

Aligned prion sequences from diverse organisms have given non-standard phylogenetic trees. Is this attributable to a paradox in prion evolution or just mis-use of homology software? By clamping homology software to the correct tree and applying only between anchors, fine details of prion evolution can be more reliably ascertained. Posted 24 Dec 96; revised 7 Feb 97.

** Therapy for nvCJD A systematic approach to a drug for CJD (and other disorders) does not quite require knowing normal function. Basically, interactive sequencing pulls back the prion gene to simpler organisms where binding sites and function are easier to determine or likely to be already known. Then reactive and specific ligand analogues are incrementally pushed forward. For prions, the idea is to covalently block oligomeric growth sites, along the lines of what Antarctic fish do with incipient blood ice crystals. Note that Inactivated normal prion is replaced within hours through de nova synthesis; dietary prp-sc is not; so this provides a fresh start. Posted 10 Feb 97; revised 12 Feb 97.

** Prion dipoles and conformation: Prion surface charge is asymmetrically distributed, giving rise to positive and negative halves to the 3D protein disk. The positive face may bind to membrane phospholipid bilayer, orienting the negative face outwards. Alternatives are explored, involving the large dipole moment produced by the coherent separation of charge interacting with the usual dipoles associated with the alpha helices (major color graphic). An earlier helix predicted from theory is speculatively positioned to interact with helix H2. The net result could stabilize the 3D structure and/or influence binding and catalysis of small ligands at a predicted binding site. Chaotropic salts may mimic quaternary structure 'salting out' by scrapie isoform. Beautiful color graphic. Posted 22 Dec 96; revised 1 Jan 97

** Prion helical wheels: The three alpha helices of length 11, 15, and 18 of the 3D NMR structure are viewed along their axes with a view to amino acid property in human prions. An animation illustrates the Swiss Beta Zipper proposal for conversion from cellular to scrapie from of prion protein. The scrapie form might be protease resistant because a vulnerable loop region is protected now. Large color graphics. Coming soon: Kyte-Doolittle refinement of the helical wheels as averaged over 34 species. Table, animation, three color graphics. Posted 22 Dec 96; last revised 3 Jan 97

** Estimating the extent of the nvCJD epidemic: It can't be done, despite claims to the contrary. Here's why, from an assumption-free, first principles mathematical approach to discrete differential equations. Posted 20 Dec 96

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