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At least 37 records · Page 2Linked to original sources
PubMed2026

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions.

In signaling cascades, signaling proteins often encode multiple domains or motifs, which presents the possibility for avidity -- where multivalent binding drastically increases interaction strength and duration. However, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphosphorylated partners as a multivalent archetype, which encompasses key secondary messengers in tyrosine kinase signaling networks. Theoretical modeling suggests that maximum avidity occurs with closely spaced tyrosine phosphorylation sites combined with moderate monovalent affinities - exactly around the innate range of SH2 domain affinity - or with phosphorylation sites separated by sufficiently flexible linkers. Surprisingly, despite sequence diversity, structure-based analysis showed relatively conserved three-dimensional spacing between SH2 domains across all tandem SH2 families, which we corroborate experimentally, suggesting evolutionary optimization for avidity interactions. The combination of structure-based analysis of domain spacing with available monovalent experimental data appears, along with iterative experimental refinement of biophysical parameters, can identify high affinity interactions of tandem SH2 domain recruitment to the EGFR C-terminal tail. Using these principles, we extended bivalent predictions into the full phosphoproteome space and structural parameterization of other partners of SH2 domain binding, providing resources and methods for more rapid expansion of bivalent analysis. These approaches lay the groundwork for larger utility in multivalent prediction and testing to help better understand protein interactions that drive cell signaling.

BLI↗
PubMed2025

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions.

In signaling cascades, where domain-motif interactions tend to interact with relatively low affinity (allowing for reversibility), signaling proteins often encode multiple domains or motifs, which present the possibility of avidity - drastically increasing the interaction strength and duration as a result of multivalent binding. However, given the large combinatorial space, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphosphorylated partners as a multivalent archetype, which encompasses key secondary messengers in tyrosine kinase signaling networks. While certain multivalent interactions have been shown to be necessary in immune receptor recruitment of partners, bivalent recruitment of tandem SH2 domains more broadly is poorly understood. Theoretical modeling suggests that maximum avidity occurs with closely spaced or flexibly linked phosphotyrosine sites, combined with moderate monovalent affinities - exactly around the innate range of SH2 domain affinity. Surprisingly, despite sequence diversity, structure-based analysis showed remarkably conserved three-dimensional spacing between SH2 domains across all tandem SH2 families, which we corroborate experimentally, suggesting evolutionary optimization for avidity interactions. The combination of structure-based analysis of domain spacing with available monovalent experimental data appears to be sufficiently accurate to predict and rank order high affinity interactions of tandem SH2 domain recruitment to the EGFR C-terminal tail. These approaches lay the groundwork for larger utility in multivalent prediction and testing to help better understand protein interactions that drive cell signaling.

BLI↗
PubMed1976

Hormone receptor mobility and catecholamine binding in membranes. A theoretical model.

[3H]-Catecholamine binding to intact cells, isolated cell membranes, and to several isolated macromolecules has been shown by several laboratories to be neither stereospecific nor inhibited by known beta-antagonists. Since additional evidence indicates that this binding is not an artifact (i.e. due neither to the binding of a catecholamine oxidation product nor hormone binding to a catabolic enzyme such as COMT), the question remains as to whether this represents binding to a bona fide membrane receptor. Because all ligands which bind strongly or compete for this binding possess a catechol group, one possible explanation is that the binding affinity is primarily determined by the catechol moiety, whereas the correct stereoisomer of the side chain is necessary to activate the receptor. Thus, although binding is a necessary condition for hormone action, the necessary and sufficient condition for activation of adenyl cyclase is both the catechol group and the correct stereoisomer of the side chain. A theoretical model is developed here to provide a quantitative basis for this hypothesis. This model extends the current concept of distinct subunits in the adenyl cyclase system by separating the receptors from the catalytic sites and placing them at separate locations within the membrane. Utilizing the spare receptor model of Furchgott, and the mobility of macromolecules within a "lipid sea," the appropriate equations to predict both hormone binding and enzyme activation are derived. Using the observed affinity constants from catecholamine binding studies, it is then shown that this model can predict the experimental observation and hence explain the apparent dichotomy arising from binding enzyme activation studies.

Animals↗
PubMed1977

Some properties of a "G0" -model of the cell cycle. II. Natural constraints on the theoretical model in exponential growth conditions.

The two-phase (G and C phases) model first proposed by Burns & Tannock (1970) to describe the cell cycle kinetics has the major advantage of requiring only two parameters for a complete description of the kinetic behaviour of populations that are in a steady-state, or that grow exponentially (with no cell loss from the population). Steady-state populations were examined in paper I of this series. Exponential populations with no cell loss are investigated here. The model assumes two basic kinetic states--a 'C' phase which includes S, G2, M and perhaps part of G1, and a 'G' phase which cells enter after completing the C-phase and from which either are lost or return to C-phase randomly. The model assumes that transit time through C-phase is constant for all cells in the population. An original method is described which allows the determination of two independent parameters of the model from the experimental 'fraction of labelled mitoses' (FLM) curve; From those two parameters, the ratio of G-cells among the total number of cells (NG/N) has been calculated for each cell population studied, The range of the NG/N values thus obtained is fairly restricted, and the mean NG/N value for exponential growths is not statistically different from that found in steady-states considering in that case the only sub-population of cycling cells (i.e. the cells that will undergo a further mitosis).

Animals↗
PubMed1977

[Scientific theoretical models in dentistry].

Developments leading to modern medicine only began about 150 years ago. The foundation of this progress was laid by the introduction of scientific working methods into practical and theoretical medicine. The principal methodical procedures are described in the present work, defined and examined as to its scientific basis. Examples from dental, oral, and maxillo-facial surgery are given as proof that the models used in the definition of present day biological research are helpful not only give accuracy to content recognized by scientific method but also to assure transition from theoretical to practical science.

Dental Articulators↗
PubMed1976

Theoretical model of ruminant adipose tissue metabolism in relation to the whole animal.

Based on theoretical considerations and experimental data, estimates of contributions of adipose tissue to energy expenditures in a lactating cow and a growing steer were developed. The estimates indicate that adipose energy expenditures range between 5 and 10% of total animal heat production dependent on productive function and diet. These energy expenditures can be partitioned among maintenance (3%), lipogenesis (1-5%) and lipolysis and triglyceride resynthesis (less thatn 1.0%). Specific sites at which acute and chronic effectors can act to produce changes in adipose function, and changes in adipose function produced by diet and during pregnancy, lactation and aging were discussed with emphasis being placed on the need for additional, definitive studies of specific interactions among pregnancy, diet, age, lactation and growth in producing ruminants.

Adipose Tissue↗
PubMed1976

A theoretical model of the respiratory function of blood.

The model of the respiratory function of blood as outlined here is judged to be a powerful tool for the evaluation of the potential effects of changes in blood as well as tissue parameters upon the supply of oxygen to tissue. The erythrocyte-plasma disequilibria in lung and systemic capillaries which is a consequence of the slowness of plasma CO2 hydrolysis are not significant in terms of the delivery of oxygen to tissue, but result in slightly lower unloading of CO2 in the lungs compared to that which might occur at full equilibration. However, the effects might be of greater interest when relating pH values measured by in vivo sampling to actual values prevailing within the capillaries. The physiological importances of hyperventilation and elevated DPG levels in anemia cannot as yet be clarified. If anything, it appears that increased DPG is a compensatory mechanism to restore proper O2-Hb affinity in alkalosis, while the purpose for an alkalosis is not obvious.

Anemia↗
PubMed1979

Bacteriorhodopsin in liposomes. II. Experimental evidence in support of a theoretical model.

In the preceding article equations describing relevant ion flows in illuminated suspensions of bacteriorhodopsin liposomes have been derived. Here these equations are subjected to experimental tests. Changes in permeability characteristics of the liposomal membrane are brought about by addition of specific ionophores and change of medium composition. Using light-driven proton uptake and electrochemical potential differences for protons across the membrane as observation parameters, ridig attempts to falsify the derived equations are unsuccessful. Agreement between equations and experimental results is established on the point of: (i) the antagonistic effect of valinomycin and nigericin on the two components of the proton-motive force, (ii) the time dependence of the changes in transmembrane electrical and chemical potential differences after the onset of illumination. In three independent experimental systems evidence was obtained for the correctness of the postulated dependence of the turnover rate of the photochemical cycle on back pressure by the transmembrane electrochemical potential difference for protons.

Bacteriorhodopsins↗
PubMed1979

A theoretical model for lipid mixtures, phase transitions, and phase diagrams.

We present a new model for the thermodynamic properties of lipid bilayers. The model consists of a system of hard cylinders of varying radii that correspond to the different molecular radii of lipids having different numbers of gauche rotations in their chains. Scaled particle theory is used to provide an accurate estimate of the entropy of packing of the cylinders. To apply the model to bilayers we introduce a semiempirical attractive potential energy. Once the form of this potential is chosen, we adjust one parameter, the interaction strength, so that the model fits the transition temperatures and entropies for various phospholipids. The model then agrees quite well with other published data for these systems. We also directly generalize our model to lipid mixtures, and we obtain phase diagrams that we compare to existing data for these systems. We use the model to describe lipid protein interactions in bilayers as well.

Lipid Bilayers↗
PubMed1976

Presynaptic calcium currents and their relation to synaptic transmission: voltage clamp study in squid giant synapse and theoretical model for the calcium gate.

A voltage clamp study of the presynaptic terminal in squid stellate ganglion has given quantitative results relating inward Ca2+ current to presynaptic membrane potential and postsynaptic response to inward Ca2+ current. The results indicate an S-shaped curve for the relationship between presynaptic potential and Ca2+ current and a linear relationship between Ca2+ current and postsynaptic potential. A similar S-shaped curve was found for the time-dependent properties of the Ca2+ conductance. Based on these results a mathematical model was developed which accounts for the experimental results in this and previously published papers by other authors. The model suggests that five subunits are involved in the Ca2+ gate and that the subunits change noncooperatively from an inactive to an active form upon membrane depolarization.

Animals↗
PubMed1977

Early chemical evolution of nucleic acids: a theoretical model.

Recent experimental work suggests a possible cyclical pathway for early prebiotic oligonucleotide formation that involves (i) dry-state (nontemplate) synthesis of random copolymers with mixed 2',5' and 3',5' bonds, (ii) passage of these oligomers into solution at low temperatures, and (iii) a preferential hydrolysis of the 2',5' bond in any short helices that have formed. This early system could have selected for complementary sequences that were largely 3',5'-linked, but may not have selected efficiently for a single enantiomer of ribose.

Cold Temperature↗