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C DeLisi

Publications and source records attributed to C DeLisi.

At least 73 records · Page 4Linked to original sources
PubMed1984

Prediction of protein function from sequence properties. Discriminant analysis of a data base.

The protein superfamilies in the National Biomedical Research Foundation sequence data base cluster into six groups that can be distinguished on the basis of four variables characterizing amino acid composition and local sequence properties. The variables are average hydrophobicity, net charge, sequence length and periodic variation in hydrophobic residues along the chain. The clusters they distinguish are: globins; chromosomal proteins; contractile system proteins and respiratory proteins other than cytochromes; enzyme inhibitors and toxins; enzymes except hydrolases; and all other proteins. The overall probability of correctly allocating a given protein to one of these functional groups is 0.76, with the allocation reliability being highest for globins (0.97) and for chromosomal proteins (0.93).

Amino Acid Sequence↗
PubMed1984

Inhibition of plaque-forming cells with anti-idiotope or hapten: variation due to hapten density on indicator red cells.

Phosphorylcholine (PC)-specific antibody plaque-forming cells (PFC) were enumerated in the spleen of BALB/c mice immunized with S. pneumoniae R36a bacterial vaccine. Two indicator red blood cells were compared: RBC coupled with the hapten, PC-RBC, and cells coupled with PC-bearing polysaccharide from the pneumococcus, PnC-RBC. Equal numbers of direct (IgM) PFC were detected with both types of indicator cells. However, a significant difference appeared in the attempt to inhibit the respective PFC either with hapten (monovalent PC chloride, PCCl) or with monoclonal antibodies against T15 idiotopes (anti-Id). At optimal coupling concentrations, inhibition of anti-PnC-RBC plaques required a 10-fold higher concentration of the hapten when compared to anti-PC-SRBC plaques. Also, the inhibition of anti-PnC-SRBC plaques with anti-Id required much higher concentration of the antibody. The phenomenon may be explained by a higher epitope density on PnC-RBC than on PC-RBC. Heavily coupled PC-RBC were more difficult to inhibit (much like the PnC-RBC) by either the hapten or the anti-Id than lightly coupled PC-RBC. A mathematical analysis of the experimental curves supports the notion that under the assay conditions used, inhibition by either the hapten or the anti-Id is influenced primarily by antibody secretion rate and epitope density on indicator cells. If the 2 variables are too high, a significant inhibition of PFC with a low affinity anti-Id may not be possible. The theory also predicted that addition of a small amount of hapten into the assay would be roughly equivalent to secretion rate reduction and would facilitate the plaque inhibition by anti-Id. Indeed, we show a synergism between a minute (non-inhibitory) amount of PCCl and anti-Id in the inhibition of PC-specific PFC. These results point out that the detection of an idiotype-bearing PFC by plaque-inhibition assay is greatly influenced by technical variation in the assay, in particular, the preparation of the indicator red cells.

Animals↗
PubMed1984

Computer analysis and structure prediction of nucleic acids and proteins.

We have developed an integrated computer system for analysis of nucleic acid and protein sequences, which consists of sequence and structure databases, a relational database, and software for structural analysis. The system is potentially applicable to a number of problems in structural biology including predictive classification of the function and location of oncogene products.

Amino Acid Sequence↗
PubMed1984

Receptor-mediated endocytosis: a model and its implications for experimental analysis.

We present a mathematical model for analyzing, simulating, and quantitating the dynamic and steady-state characteristics of receptor-mediated endocytosis. The basic processes considered by the model are ligand-receptor binding, diffusion of receptors and ligand-receptor complexes in the plane of the membrane toward and away from coated pits, binding of ligand-receptor complexes to coated pit proteins, endocytosis of coated pit contents, degradation of ligand, and recycling of undegraded receptors. The model accounts quantitatively for a wide variety of kinetic data and makes new predictions about steady-state characteristics. We show that for homogeneous receptors the slope of the Scatchard plot is not necessarily constant but can have a positive or negative derivative, depending on the concentration of coated pit proteins and their reactivity. This finding suggests that binding data, which show linear and concave curves, might be explainable be a simple coated pit-related mechanism. Similarly the relationship between the x-intercept and the number of receptors is also affected by kinetic parameters controlling endocytosis. We briefly discuss these results in terms of possible mechanisms for the action of tumor promoters, the large variations in receptor number and affinity in the literature, and methods for quantitative characterization of parameters.

Animals↗
PubMed1983

Thymus-independent immunogenicity in vitro of the divalent antigen DNP-polyethylene oxide.

Chemically simple and physically well-defined dinitrophenyl derivatives of polyethylene oxide (DNP-PEO) can be prepared in a wide range of forms and sizes. These materials were used to investigate the molecular basis of immunogenicity and the binding of the antigens to membrane-bound receptors. Both di- and multivalent DNP-PEO activate normal murine B lymphocytes to yield primary anti-DNP antibody response in vitro. The immunogenicity is dependent on the carrier chain length but independent of T cells. Responses comparable to those induced by DNP-conjugated polymerized flagellin are induced by divalent linear materials of medium molecular weights of about 60,000. A highly multivalent material is moderately immunogenic, but at much lower antigen doses than divalent materials. The carrier PEO does not affect B-cell responses to DNP-PEO or T-cell response to succinyl concanavalin A. Moreover, it shows no polyclonal mitogenicity at concentrations as high as 1 mg/ml. Studies of antigen binding to cell surface DNP receptors show that the strongly immunogenic materials of medium molecular weights have an appreciable tendency to bind bivalently and thus potentially to crosslink receptors. The binding of smaller, less immunogenic antigen appears predominantly monovalent.

Animals↗
PubMed1983

Membrane fluidity and the probability of complement fixation.

We develop a mathematical theory of the role of membrane fluidity in the initiation of the IgG mediated complement cascade. The basic assumption is that C1q must be at least doubly bound to activate C1r, but that once C1q is doubly bound, C1r still requires some mean finite time tau to become enzymatically active. If C1q dissociates during this time interval, C1r cannot be activated. We consider the consequences of the simplest model of fluidity--one in which the difference between "fluid phase" lipids and "non-fluid phase" lipids is to allow protein mobility, but not a change in protein conformation. We show that under these conditions fluidity will effect C1r activation only if the rate of formation of multiply bound C1q is limited by diffusion in the membrane. If diffusion in the membrane is not rate-limiting, then, within the framework of this model, fluidity has no effect whatsoever on C1r activation. Thus, an experimental determination that C1q binding is not rate-limited by diffusion in the surface, but that fluidity does effect activation, would suggest a protein conformational change resulting perhaps from altered lipid composition. If diffusion in the surface does rate limit multiple C1q binding, we predict the possibility of an optimum diffusion coefficient for activation. For suitably chosen and reasonable parameter values this optimum will occur in the range (10(-11) less than or equal to D less than or equal to 10(-8) cm2/sec. We predict further, under these circumstances, a precipitous drop in the probability of activation above the optimum. The abrupt switch from a high probability of activation to essentially no probability of activation suggests the possibility of a very sensitive control mechanism exploitable by relatively small changes in membrane lipid composition.

Animals↗
PubMed1983

Analysis of the rate-limiting step in a ligand-cell receptor interaction: the immunoglobulin E system.

Theory predicts that the kinetics of simple interactions between a ligand and a receptor bound on the surface of a cell will be affected by the occupancy of receptors on the same cell. In a diffusion-limited reaction the effect will be on the rate of dissociation but not on the rate of association until the cell is virtually saturated with ligand. If the rate of reaction is not diffusion limited, then the opposite holds; i.e., the forward velocities will be proportional to the concentration of vacant receptors, but the reverse reactions will not be. We examined the kinetics of reaction between immunoglobulin E (IgE) and its receptor and clearly demonstrated that the reaction is not diffusion controlled. The substantial (congruent to 30-fold) increase in the forward rate constant observed for the reaction of IgE with solubilized receptors as opposed to cell-bound receptors is therefore not an artifact of calculation. Since the reverse rate constants show little difference, we postulate that the presence of other surface components (rather than conformational differences in the receptor) affects the reaction with the cells. As an aid to the analysis, the theory has been extended so that not only the rate constants but also the entire course of the reaction of ligand with cell receptors can be predicted for diffusion-limited vs. non-diffusion-limited interactions.

Animals↗
PubMed1983

A theory of measurement error and its implications for spatial and temporal gradient sensing during chemotaxis. II. The effects of non-equilibrated ligand binding.

Cells generally chemotax along a direction in which their receptor occupancy gradient--whether spatial or temporal--is maximum. Occupancy differentials are, however, often so small as to be masked by thermal noise; i.e., by fluctuations inherent in the stochastic nature of ligand binding. Such fluctuations therefore impose a fundamental limit on the sensitivity of a cell's ability to detect a chemoattractant gradient. In order to pursue the implications of this limit, fluctuation theories have been developed. The theories assume that the signal is some function of the receptor occupancy gradient, allow an estimate of the standard deviation about the mean signal, and permit an evaluation of, among other things, the extent to which a receptor defect can impair an effective response. Previous theories have assumed an equilibrated ligand-receptor interaction. In this paper we introduce a generalized definition of a signal caused by a receptor occupancy gradient that allows us to develop a non-equilibrium theory of thermal noise. We show that previous formulations are a special case of the current development. More specifically, we find the following. Swimming cells subject to Brownian tumbling must generally average their signals over a very long time period to achieve a signal-to-noise ratio less than or equal to 1. Spatial gradient detection is possible with ligand-receptor equilibrium constants less than 10(3)M-1, but since such ligands are rare, theory predicts that tumbling cells will generally not detect gradients by measuring spatial occupancy differentials. These conclusions hold irrespective of whether chemical equilibrium is achieved. For crawling cells not subject to Brownian tumbling, a range of affinities exists in which spatial or temporal gradient detection is possible. In general a spatial mechanism is more efficient for low affinity ligands (dissociation times less than 0.3 s), whereas a temporal mechanism is more efficient for higher K. In this case the detection of gradients in slowly dissociating ligand will be facilitated if signal processing begins prior to chemical equilibration. An important new parameter is indicated by the theory. The definitions of a temporal gradient signal is based on estimating and comparing average occupancy over two time intervals displaced by a time t1. The theory predicts an optimal t1, of order milliseconds, that leads to the shortest minimum averaging time. For t1 values at and longer than the optimum, and for all averaging times exceeding some minimum, the cell will detect a temporal signal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Mathematical modeling in immunology.

The first step in the sequence of events leading to antibody synthesis and secretion is antigen encounter by B cell receptors. The reaction leads to major membrane perturbations, including the capping and endocytosis of receptors. These events might play an important role in various aspects of the B cell response, but they are not well understood, and in any event it seems unlikely that a satisfactory explanation of response regulation to most antigens can be advanced in terms of these phenomena alone, without explicit consideration of other cell populations. Suppressor and helper T cell populations qualitatively and quantitatively regulate the response to almost all antigens. Knowledge of the antigen dose dependence of the response of these populations will undoubtedly be important for a complete understanding of major immune response phenomenology such as suppression and affinity regulation. T cell dose response patterns are currently unavailable, nor is much known of the molecular mechanisms mediating interactions among antigen responsive T cells. In order to explain why this information is important, and to connect disparate data on immunoregulation in a simple way, I introduced dose response patterns based on analogy with basophils, assumed cell interactions mediated by autoantiidiotypic antibodies, and briefly pursued the consequences. In the final section, the genetic experiments that are providing information on the molecular constraints on cell interactions were mentioned, and some of the outstanding theoretical questions were briefly discussed.

Animals↗
PubMed1982

Evaluation of reaction rate enhancement by reduction in dimensionality.

The paths followed by ligands as they react with or dissociate from cell surface receptors may include weak association with nonreceptor portions of the surface followed by lateral diffusion in the plane of the membrane to a receptor. The change in dimensionality of the diffusion process by utilization of these nonspecific paths has been invoked by a number of investigators as a mechanism for enhancing reaction rate in biological systems. This paper extends our previous work on the calculation of diffusive rate constants for ligand-receptor paths. We find that they have little effect on rate constants unless the number of free receptors per cell has been reduced to less than or equal to 10(2). This number represents better than 90% occupancy for most eukaryotes, suggesting that the dimensional change mechanism is of limited consequence. We show further that when the free receptor number is low enough for rate enhancement, then the primary parameter of consequence is D'K*/D, where D' and D are the two- and three-dimensional diffusion coefficients, respectively, and K* the nonspecific affinity. A 10-fold rate enhancement with 100 free receptors requires that this parameter be of order 10(-3). This value is barely within the lower limit imposed by currently available experimental information, casting doubt on the relevance of nonspecific paths in cellular systems.

Animals↗
PubMed1981

Mechanism of binding of multivalent immune complexes to Fc receptors. 2. Kinetics of binding.

The kinetics of association and dissociation of affinity cross-linked IgG oligomers with Fc receptors on P388D1 cells have been studied at 0 degrees C. For dimers prepared with two different affinity cross-linking reagents (DIBADL and BDPE) and also trimers and a heavy oligomer fraction prepared with BDPE, monomeric IgG accelerates the rate of dissociation of bound oligomer from the cells. This observation is consistent with a binding mechanism in which monovalently, and multivalently bound species are in rapid equilibrium with one another on the cell surface and in which the rate of formation of the divalently bound species is faster than the dissociation of the monovalent species from the cells. As predicted, the rates of dissociation of BDPE cross-linked oligomers decrease with size, and dimers (cross-linked with DIBADL) which can self-aggregate on the cell surface dissociate more slowly than nonaggregating (BDPE) dimers. The association and dissociation of oligomers with P388D1 cells proceed by parallel fast and slow processes, even with cells that bind dimers with a single affinity. The origin of this heterogeneity is not known but could arise from a fraction of receptors in environments with limited accessibility to bulk solution. The fast component of the association reaction is second order, and the rate-limiting step of this process is the formation of the monovalently bound intermediate from solution-phase oligomer.

Animals↗
PubMed1981

Ligand binding to multiple equivalent sites with steric hindrance.

A general model is developed for the binding of ligands to multiple receptor sites in which steric blockage of sites is taken into account. Analytical expressions for extent of ligand binding as a function of ligand concentration are derived employing a stochastic matrix approach. Using simple numerical techniques to evaluate these expressions it is possible to obtain the inherent affinity of each site for a ligand, the number of sites available and the number of sites excluded when a ligand binds to any site. The expressions derived here are contrasted with other expressions based on simple equilibrium considerations in which there are no interactions between sites and no interactions between ligands in different sites. It is shown that the expressions derived here predict significant departures from linearity in Scatchard plots and a strong negative cooperatively, especially toward the saturation limit.

Binding Sites↗