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PubMed1989

Possible roles of partial sequences at N- and C-termini of amelogenin in protein-enamel mineral interaction.

The purpose of this study was to assess the functional significance of homologous sequences of mammalian amelogenins at their N- and C-termini. A porcine 5-kDa fragment corresponding to the N-terminal 45 residues of amelogenins was purified from the secretory enamel. The decapeptide TDKTKREEVD corresponding to the C-terminal 10 residues of amelogenins was synthesized according to conventional solid-phase procedures. The inhibitory activity of both moieties on apatite crystal growth was determined in a supersaturated solution having an ionic composition similar to that of the fluid phase separated from porcine secretory enamel. The 5-kDa amelogenin fragment was sparingly soluble in neutral solutions and (in condensed forms because of aggregation) showed no significant inhibition of crystal growth, whereas the fragment molecules pre-adsorbed onto the seed crystals yielded modest inhibition of hydroxyapatite precipitation. However, their inhibitory activity was significantly lower than that of parent porcine amelogenin (25-kDa molecular mass). The high solubility of synthesized decapeptide allowed us to determine the adsorption isotherm onto hydroxyapatite at 37 degrees C, at an ionic strength similar to that of the enamel fluid. The obtained adsorption isotherm was described by a Langmuir model; the adsorption affinity and the maximum adsorption sites were 6.2 mL/mumol and 0.53 mumol/m2, respectively. As expected from the low adsorption affinity, the peptide showed a much weaker inhibition of apatite crystal growth than the parent amelogenin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1996

The maize gamma-zein sequesters alpha-zein and stabilizes its accumulation in protein bodies of transgenic tobacco endosperm.

Zeins are seed storage proteins that form accretions called protein bodies in the rough endoplasmic reticulum of maize endosperm cells. Four types of zeins, alpha, beta, gamma, and delta, aggregate in a distinctive spatial pattern within the protein body. We created transgenic tobacco plants expressing alpha-zein, gamma-zein, or both to examine the interactions between these proteins leading to the formation of protein bodies in the endosperm. Whereas gamma-zein accumulated in seeds of these plants, stable accumulation of alpha-zein required simultaneous synthesis of gamma-zein. The zein proteins formed accretions in the endoplasmic reticulum similar to those in maize endosperm. Protein bodies were also found in protein storage vacuoles. The accumulation of both types of zeins peaked early in development and declined during maturation. Even in the presence of gamma-zein, there was a turnover of alpha-zein, suggesting that the interaction between the two proteins might be transitory. We suggest that gamma-zein plays an important role in protein body formation and demonstrate the utility of tobacco for studying interactions between different zeins.

Enzyme-Linked Immunosorbent Assay↗
PubMed2005

Parallel development of cardiomyocytes and neurons in embryonic stem cell culture.

Recent studies suggest that there are strong parallels between development and patterning of the vertebrate vascular system and the nervous system. While previous observations reported generation of vascular and neuronal progenitors from embryonic stem (ES) cells, the question of parallel development of vascular and neuronal cells in the same culture has not yet been investigated. Mouse D3 ES cells were cultured for 4 days in differentiation medium IMDM with 15% FBS in 100 mm non-adhesive Petri dishes to allow cells to aggregate and form embryoid bodies. At day 5, fibronectin or all-trans retinoic acid with fibronectin was added to the culture. On day 9, the embryoid bodies were seeded on poly-L-ornithine/fibronectin-coated plates. After plating, half of the plates were treated with laminin for 3 days and maintained for 1 week in Neurobasal media with B27. Here we show that ES cells differentiate into interconnected rhythmically contracting aggregates of functional cardiomyocytes and neurons. Double immunofluorescence with anti-phospholamban, anti-SERCA2 antibodies to detect cardiomyocytes and with anti-MAP2 antibodies to detect neurons revealed the cell aggregates consisting entirely of cardiomyocytes with neuronal cells located on the periphery or covering the aggregate's surface. The observed concurrent development of cardiomyocytes and neurons suggests bidirectional communication between both cell types. We propose that crosstalk between cardiovascular and neuronal progenitors is an important mechanism for the development of both systems.

Animals↗
PubMed2005

Spatial patterns and species performances in experimental plant communities.

Amongst the various hypotheses that challenged to explain the coexistence of species with similar life histories, theoretical, and empirical studies suggest that spatial processes may slow down competitive exclusion and hence promote coexistence even in the absence of evident trade-offs and frequent disturbances. We investigated the effects of spatial pattern and density on the relative importance of intra- and interspecific competition in a field experiment. We hypothesized that weak competitors increased biomass and seed production within neighborhoods of conspecifics, while stronger competitors would show increased biomass and seed production within neighborhoods of heterospecifics. Seeds of four annual plant species (Capsella bursa-pastoris, Stachys annua, Stellaria media, Poa annua) were sown in two spatial patterns (aggregated vs. random) and at two densities (low vs. high) in three different species combinations (monocultures, three and four species mixtures). There was a hierarchy in biomass production among the four species and C. bursa-pastoris and S. media were among the weak competitors. Capsella and Stellaria showed increased biomass production and had more individuals in the aggregated compared to the random pattern, especially when both superior competitors (S. annua, P. annua) were present. For P. annua we observed considerable differences among species combinations and unexpected pattern effects. Our findings support the hypothesis that weak competitors increase their fitness when grown in the neighborhood of conspecifics, and suggested that for the weakest competitors the species identity is not important and all other species are best avoided through intraspecific aggregation. In addition, our data suggest that the importance of spatial pattern for the other competitors might not only depend on the position within the hierarchy but also on the identity of neighbor species, species characteristics, below ground interactions, and other nonspatial factors.

Biomass↗
PubMed2003

Forest fragmentation severs mutualism between seed dispersers and an endemic African tree.

Because bird species are lost when forests are fragmented into small parcels, trees that depend on fruit-eating birds for seed dispersal may fail to recruit seedlings if dispersal agents disappear. We tested this prediction in rainforest in the East Usambara Mountains of Tanzania, by using the endemic tree Leptonychia usambarensis (Sterculiaceae) and birds that disperse its seeds. We investigated bird abundance and Leptonychia dispersal ecology in fragments isolated for >70 yr, as compared with 3,500 ha of continuous forest. Birds that dispersed Leptonychia seeds in continuous forest were rare or absent in small fragments, where fewer seeds were removed from each tree, far fewer seedlings occurred >10 m from parent trees, and far more seedlings occurred in dense aggregations under parental crowns. Overall, our samples showed that fewer juvenile Leptonychia recruited in fragments than in continuous forest. We provide solid evidence that deficient dispersal due to habitat fragmentation seriously impacts the reproductive cycle of a tropical bird-dispersed tree.

Animals↗
PubMed1986

Characteristics of bovine parathyroid cell organoids in culture.

Adult bovine parathyroid glands were enzymatically dispersed and groups of 2 to 5 million cells were reassociated into multicellular aggregates (organoids) by rotation in roller tubes in serum-free medium. Fifty to seventy percent of the seeded cells were incorporated into each organoid at 3 d of culture, and in a typical experiment where DNA content was assayed before and after culture 49 +/- 3% of the original seeded DNA was present after 19 d of culture. No significant differences in DNA content were observed between experimental groups at any time of culture. The morphology of the cells in organoids was similar to that of cells in fresh tissue as determined by light and electron microscopy. The organoids secreted intact parathyroid hormone (PTH) and COOH-terminal hormone fragments which were similar to those released from monolayer cell cultures. Organoids maintained the ability to modulate PTH secretion in response to extracellular calcium for over 2 wk in culture. Each organoid was cultured separately and secreted PTH such that the mean standard deviation of secretion within groups on a per organoid basis was 16.3% of the mean. Using a perifusion system to study acute regulation over a 2-wk period of culture, PTH secretion was suppressed 58 +/- 4% by 2.5 mM compared to that at 0.25 mM calcium. To examine PTH secretion over a range of calcium concentrations, the perifusion system was used to apply 4-h linear gradients of decreasing calcium to fresh tissue slices and to organoids. The results indicated that the calcium (ionized) concentration at 50% secretory suppression (set-point) were 1.30 +/- 0.11 and 1.20 +/- 0.9 mM for the organoids and slices, respectively. Acute secretory control by calcium decreased after 14 d and was not detectable at 22 d of culture. The results demonstrated that the organoids maintained their differentiated function and tissuelike morphology for extended periods in vitro and therefore represent a suitable model system for studies on the long-term modulation of PTH secretion by vitamin D metabolites, ions, and other agents.

Animals↗
PubMed2006

[Effects of extracts from different parts of Folium perillae (L.) Britt. on Hemorrheological parameters in rats].

In order to provide experimental data for the development and application of drug in clinic, we determined the effects of extracts from different parts of folium perillae (L. ) Britt. on hemorheological parameters, extracted from leaves (folium perillae), seeds (fructus perillae) and peduncles (caulis perillae). The results showed that all extracts from different parts of folium perillae (L. ) Britt. can significantly reduce the whole blood viscosity at low shear rate (10 s(-1)), erythrocyte aggregation index, erythrocyte electrophoresis index (P<0.05), and the whole blood reductive viscosity at low shear rate (10 s(-1)) (P<0.01). Extracts from folium perillae and caulis perillae can significantly decrease erythrocyte deformation index (P<0.05), whereas extracts from fructus perillae can not. Extracts from fructus perillae and caulis perillae can significantly decrease plasma viscosity at low shear rate(10 s(-1)), but extracts of folium perillae can not. Aspirin can only decrease the whole blood reductive viscosity at low shear rate and plasma viscosity (P<0.05). All extracts from different parts of folium perillae (L. ) Britt. had no significant effects on hematocrit, erythrocyte rigidity index, fibrinogen concentration , the whole blood viscosity and the whole blood reductive viscosity at middle and high shear rate (60 s(-1),120 s(-1)).

Animals↗
PubMed1983

The beriberi analogy to myocardial infarction.

Two pandemics of heart attack deaths have plagued the world's population during the past 130 years. The first pandemic, induced by beriberi, was caused by the industrial revolution altering the nutritional composition of rice. By 1892 a simple working knowledge, then at hand, could have terminated the beriberi plague; however, orthodox medicine being then enchanted with the false concept that all disease was caused by germs, permitted millions of Asians to die needlessly of beriberi by refusing to tell them to eat rice bran or to drink rice bran tea. A second pandemic of heart attack deaths, called myocardial infarction (MI), struck the developed nations of the Western World in full force after 1930. As a hypothesis, it is suggested that this MI pandemic, still raging today, was caused by a change in food processing that occurred after 1920, when the new oil seed industry introduced into our food three greatly harmful lipid substances. The unnatural trans-trans isomer of linoleic acid, which had never been in human food prior to 1920 and which entered our food in margarines and refined oils, blocked the conversion of natural cis-cis linoleic acid to prostaglandin E1, which tends to prevent MI, both by acting as a vasodilator and by minimizing platelet aggregation. Harmful lactones were also introduced into our food, increasing the risk of MI by decreasing the fibrinolytic activity of our blood. The oil seed industry also introduced into our diet free radical lipid peroxides that make the myocardium more vulnerable to infarction. It is suggested that except for the one in 500 of us who is afflicted by familial hypercholesterolemia, the cholesterol concept of MI is as false today as was the concept in 1900 that germs caused beriberi. It is further suggested that a working knowledge is at hand today that can make death from MI just as rare as death is now from a beriberi-induced heart attack.

Animals↗
PubMed2006

Solution synthesis of germanium nanowires using a Ge2+ alkoxide precursor.

A simple solution synthesis of germanium (Ge0) nanowires under mild conditions (<400 degrees C and 1 atm) was demonstrated using germanium 2,6-dibutylphenoxide, Ge(DBP)2 (1), as the precursor where DBP = 2,6-OC6H3(C(CH3)3)2. Compound 1, synthesized from Ge(NR2)2 where R = SiMe3 and 2 equiv of DBP-H, was characterized as a mononuclear species by single-crystal X-ray diffraction. Dissolution of 1 in oleylamine, followed by rapid injection into a 1-octadecene solution heated to 300 degrees C under an atmosphere of Ar, led to the formation of Ge0 nanowires. The Ge0 nanowires were characterized by transmission electron microscopy (TEM), X-ray diffraction analysis, and Fourier transform infrared spectroscopy. These characterizations revealed that the nanowires are single crystalline in the cubic phase and coated with oleylamine surfactant. We also observed that the nanowire length (0.1-10 microm) increases with increasing temperature (285-315 degrees C) and time (5-60 min). Two growth mechanisms are proposed based on the TEM images intermittently taken during the growth process as a function of time: (1) self-seeding mechanism where one of two overlapping nanowires serves as a seed, while the other continues to grow as a wire; and (2) self-assembly mechanism where an aggregate of small rods (<50 nm in diameter) recrystallizes on the tip of a longer wire, extending its length.

Germanium↗
PubMed2004

The history of the plant embryo. Terminology and visualization from ancient until modern times.

Since ancient times comparisons between embryonic forms of humans, animals, and plants are known. In deciphering a plant embryo and its development, one applied a specific zoomorphic terminology. Until the 17th century naturalists who studied plants were inspired by the concepts of ancient natural philosophy. Since then plant embryos are visualized by drawings and diagrammatic sketches. In the 18th century the embryo became an important issue in debates concerning theories of generation and the analogy between animal egg and vegetable seed was emphasized. Due to the cell theory and refined microscopic techniques around 1850 botanists described the 'plant embryo' as an aggregate of cells. The 20th century profited of further technical improvements, e.g. microphotography, SEM, and plant tissue culture. The spell of the word embryo integrated morphological and morphogenetic data in botany and served as a code to decipher botanic forms. The paper presents a short history of the concept of 'plant embryo' and focuses on its distinct meanings over centuries, supported by different images.

Embryology↗
PubMed1996

Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.

In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.

Alzheimer Disease↗
PubMed1983

The effect of aspirin and linoleic acid on platelet aggregation, platelet fatty acid composition and haemostasis in man.

The effect of linoleic acid and of aspirin on platelet aggregation has been measured in six healthy volunteers with a new platelet aggregometer (Wellcome) designed to be used with whole blood. The subjects were given a controlled diet for 6 weeks during which their platelet aggregation, platelet fatty acid composition, dilute blood clot lysis time, bleeding time and serum cholesterol and triglycerides were measured. A basal diet typical of that normally eaten in the UK was fed for 3 weeks, then for a further 2 weeks 60 ml/d of safflower seed oil was added to the diet. Finally there was a further week on the basal diet and on the last day the subjects each took 900 mg of aspirin. The effects of the safflower seed oil was to increase platelet linoleic acid (C18:2 omega 6) content from 5.53 +/- 0.52 micrograms to 10.1 +/- 0.92 micrograms/100 micrograms total fatty acids (P less than 0.001), to decrease platelet aggregation to ADP, and to decreased serum cholesterol. Fibrinolysis and bleeding times were unaltered. Aspirin decreased platelet aggregation, prolonged bleeding time and increased platelet arachidonic acid (C20:4 omega 6) from 24.7 +/- 0.38 micrograms to 25.8 +/- 0.61 micrograms/100 micrograms total fatty acids (P less than 0.01). The Wellcome whole blood aggregometer is a sensitive test of platelet function and using it linoleic acid has been shown to reduce aggregation in conjunction with an increase in polyunsaturated fatty acid content of the platelet membrane.

Adult↗
PubMed1991

Hyaluronan interactions with hydroxyapatite do not alter in vitro hydroxyapatite crystal proliferation and growth.

The interaction of hyaluronan (Mr range 80-120 x 10(4)) with poorly crystalline hydroxyapatite, such as is found in calcified cartilage and bone, was studied to challenge the hypothesis that free hyaluronan found in proteoglycan aggregate preparations could affect in vitro mineralization. Using a Langmuir adsorption isotherm, based on uronic acid content, hyaluronan was found to bind to hydroxyapatite with an affinity K of 0.12 ml/microgram uronate and N = 6.8 micrograms uronate/m2 hydroxyapatite binding sites. This is contrasted with K = .047 ml/microgram uronate and N = 9.0 micrograms uronate/m2 for a bovine nasal proteoglycan monomer preparation. Although the proteoglycan monomer and aggregate preparations have been reported to inhibit hydroxyapatite growth at concentrations of 1 mg/ml, using solution concentrations of 0, 0.01, 0.1 and 1 mg/ml hyaluronan there were no detectable alterations in the rate of seeded hydroxyapatite growth and proliferation. These data indicate that although in vitro hyaluronan may bind with weak affinity to hydroxyapatite, this interaction does not affect mineral growth, and the presence of hyaluronan would not contribute to the increased inhibitory potential of cartilage proteoglycan aggregate relative to monomer preparations.

Adsorption↗
PubMed2007

Human hepatoblast phenotype maintained by hyaluronan hydrogels.

Human hepatoblasts and hepatic stem cells, pluripotent hepatic progenitors that give rise to hepatocytes and biliary cells, were isolated from fetal livers and found to express hyaluronan receptors (CD44) in both the freshly isolated cells and after culture. This implicates an in vivo connection to hyaluronan (HA), an embryonic matrix component, as a candidate 3-dimensional (3-D) scaffold for hepatic progenitor cell expansion and/or differentiation. To assess HAs as scaffolds, hepatoblasts and hepatic stem cells were seeded into HA hydrogels with a serum-free, hormonally defined medium tailored for expansion of hepatic progenitors. Cell aggregates formed within the HA hydrogels and remained viable, proliferative, and demonstrated a stable phenotype intermediate between that of hepatic stem cells and hepatoblasts throughout more than 4 weeks of culturing, with little evidence of lineage restriction towards either hepatocytic or biliary pathways. The phenotype consisted of stable co-expression of both hepatocytic and biliary markers such as biliary-specific cytokeratin, CK19, low levels of expression of albumin, and urea synthesis. HA hydrogels are ideal as 3-D scaffolds for pluripotent hepatic progenitors and should be useful for generating cells to be used in bioartificial livers or tissue engineered liver grafts.

Albumins↗
PubMed2006

Biofabricated marine hydrozoan: a bioactive crystalline material promoting ossification of mesenchymal stem cells.

This study introduces a novel three-dimensional biomatrix obtained from the marine hydrocoral Millepora dichotoma as a scaffold for hard tissue engineering. Millepora dichotoma was biofabricated under field and laboratory conditions. Three-dimensional biomatrices were made in order to convert mesenchymal stem cells (MSCs) to exemplify osteoblastic phenotype. We investigated the effect of the biomatrices on MSCs proliferation and differentiation at 2, 3, 4, 7, 10, 14, 21, 28, and 42 days. Different analyses were made: light microscopy, scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS), calcium incorporation to newly formed tissue (alizarin red), bone nodule formation (von Kossa), fat aggregate formation (oil red O), collagen type I immunofluorescence, DNA concentrations, alkaline phosphatase (ALP) activity, and osteocalcin concentrations. MSCs seeded on Millepora dichotoma biomatrices showed higher levels of calcium and phosphate incorporation and higher type I collagen levels than did control Porites lutea biomatrices. ALP activity revealed that MSCs seeded on M. dichotoma biomatrices are highly osteogenic compared to those on control biomatrices. The osteocalcin content of MSCs seeded on M. dichotoma remained constant up to 2 weeks before rising to surpass that of seeded P. lutea biomatrices after 28 days. Our study thus showed that M. dichotoma biomatrices enhance the differentiation of MSCs into osteoblast and hence have excellent potential as bioscaffold for hard tissue engineering.

Alkaline Phosphatase↗
PubMed2025

Leveraging bioorthogonal conjugation for alpha synuclein fibril surveillance.

Alpha synuclein (&#x3b1;-syn) amyloid fibrils are associated with various neurodegenerative diseases. To better understand the molecular and cellular basis for &#x3b1;-syn fibril persistence and spread, we implemented a fluorophore labeling strategy to surveil pre-formed &#x3b1;-syn fibrils in solution and in cells. We leveraged amber codon mediated incorporation of a tetrazine-based artificial amino acid (TetV2.0) to install a cyclooctene-conjugated Janeliaflour, JF549, at four sites on human &#x3b1;-syn: residues 4, 60, 96 and 136. Fast coupling occurred under mild buffer conditions and in the presence of the disease-associated cofactor and cytotoxic lipid, psychosine. Labeled fibrils retained their polymorphic features, seeded the growth of new fibrils in vitro, and induced the seeding of positive puncta in &#x3b1;-syn FRET biosensor HEK293T cells. This allowed simultaneous tracking of exogenous and endogenous &#x3b1;-syn aggregates in biosensor cells, and their localization within the cells. In doing so, our approach facilitates more detailed mechanistic investigation of &#x3b1;-syn aggregates.

Synuclein↗
PubMed2004

Novel biodegradable cholesterol-modified polyrotaxane hydrogels for cartilage regeneration.

Cholesterol was introduced to a hydrolyzable polyrotaxane (PRx), not only to improve cell proliferation and glycosaminoglycan (GAG) production, but also to control the degradation rate of the hydrogels. The cholesterol was introduced to hydrolyzable PRx species by threading many alpha-cyclodextrins (alpha-CDs) on a poly(ethylene glycol) (PEG) chain having hydrolyzable ester linkages at the terminals; the PRx species were then cross-linked with other PEGs to prepare cholesterol-modified PRx hydrogels. The degree of cholesterol substitution was varied in the range of 1-25%. These hydrogels were examined to clarify the effect of cholesterol groups on mechanical properties, erosion time and chondrocyte proliferation. Highly porous biodegradable cholesterol-modified PRx hydrogels were fabricated using a combination of potassium hydrogen carbonate (as an effervescent salt) and citric acid. This fabrication process enabled the homogeneous expansion of pores within the polymer matrices, leading to well-interconnected macroporous hydrogels with a mean pore size of around 200-400 microm, ideal for high-density chondrocyte seeding. Time to complete degradation of the hydrogels was shortened by increasing the degree of substitution due to the aggregation of alpha-CDs through hydrophobic interaction of cholesterol groups. The presence of approx. 10% cholesterol improved the chondrocyte proliferation and GAG production. The modification of cholesterols to PRx is a good approach for creating new biodegradable hydrogels in terms of chondrocyte culture and controlling degradation time of the hydrogels.

Animals↗
PubMed2006

Structural stability and dynamics of an amyloid-forming peptide GNNQQNY from the yeast prion sup-35.

A seven amino acid yeast prion sup-35 fragment (GNNQQNY) forms amyloid fibrils. The availability of its detailed atomic oligomeric structure makes it a good model for studying the early stage of aggregation. Here we perform long all-atom explicit solvent molecular simulations of various sizes and arrangements of oligomer seeds of the wild-type and its mutants to study its stability and dynamics. Previous studies have suggested that the early stage rate-limiting step of oligomer formation occurs in high-order oligomers. Our simulations show that with the increase in the number of strands even from a dimer to a trimer, oligomer stability increases dramatically. This suggests that the minimal nucleus seed for GNNQQNY fibril formation could be small and is likely three or four peptides, in agreement with experiment, and that higher-order oligomers do not dissociate quickly since they have small diffusion coefficients and thus slow kinetics. Further, for the hydrophilic polar GNNQQNY, there are no hydrogen bonds and no hydrophobic interactions between adjacent beta-sheets. Simulations suggest that within the sheet, the driving forces to associate and stabilize are interstrand backbone-backbone and side chain-side chain hydrogen bonds, whereas between the sheets, shape-complementary by the dry polar steric zipper via the side chains of Asn-2, Gln-4, and Asn-6 holds the sheets together, as proposed in an earlier study. Since the polar side chains of Asn-2, Gln-4, and Asn-6 act as a hook to bind two neighboring sheets together, these geometric restraints reduce the conformational search for the correct side chain packing to a two-dimensional problem of intersheet side chain interactions. Mutant simulations show that substitution of Asn-2, Gln-4, or Asn-6 by Ala would disrupt this steric zipper, leading to unstable oligomers.

Amino Acid Sequence↗