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Biomedical subjects

J Wyman

Publications and source records attributed to J Wyman.

At least 19 recordsLinked to original sources
PubMed1992

Symmetry conditions for binding processes.

Symmetry conditions are derived for global and local binding processes in biological macromolecules. It is shown that the conditions applying in the case of the macromolecule as a whole are decoupled from those referring to individual sites. In the case of two sites, the global binding curve is always symmetric, and the individual-site binding curves are always asymmetric, unless the two sites are identical or independent. In the case of three sites or more, individual-site binding curves can show symmetric or asymmetric behavior. The conditions derived for symmetry in the local description of binding processes also apply to the case of linkage among different ligands and to steady-state kinetics. Application to the analysis of oxygen binding to human hemoglobin under physiological conditions provides a model-independent interpretation of the asymmetric nature of the binding curve. Asymmetry of the global binding curve can coexist with symmetric or asymmetric binding to the individual alpha and beta chains. If the binding curves of the two chains are symmetric, then subunit heterogeneity and asymmetric interactions must exist in the hemoglobin tetramer. On the other hand, if the binding curves of the two chains are asymmetric, then subunit heterogeneity and asymmetric interactions are not necessary for global asymmetric binding.

Allosteric Regulation↗
PubMed1978

Aggregation effects on oxygen binding of sickle cell hemoglobin.

Deoxygenation of concentrated solutions (0.33 gram per milliliter) of sickle cell hemoglobin show (i) a "crisis point" where the oxygen binding curve is unusually steep (Hill coefficient of 5 to 6), and (ii) a simultaneous increase in light scattering. Nearly identical oxygen binding curves are obtained upon oxygenation and deoxygenation of these solutions. The influence of aggregation is to shift the curve toward higher pressures.

Allosteric Regulation↗
PubMed1978

Analysis of ligand binding curves in terms of species fractions.

The ligand binding curve for a macromolecular system presents the average number of ligand molecules bound per macromolecule as a function of the chemical potential or the logarithm of the ligand concentration. We show that various observable properties of this curve, for example its asymptotes and derivatives, are expressible in terms of linear combinations of the mole fractions alphai of macromolecules binding i molecules of ligand. Whenever enough such properties of the binding curve are known, the linear equations in alphai can be solved to give the mole fractions of each of the various macromolecular species. An application of these results is that a Hill plot for hemoglobin-ligand equilibrium where the asymptotes approach unit slope can be made to yield the four Adair constants by a simple algebraic method. A second use is that a knowledge of the first and second derivatives of the binding curve at points along the curve can yield the species fractions as functions of the degree of saturation without direct knowledge of the ligand binding constants. These methods are illustrated by some numerical examples.

Binding Sites↗
PubMed1978

The place of symmetry in the study of biological macromolecules.

The various aspects of symmetry involved in discussions of biological macromolecules are analysed. Among these are geometrical symmetry of the macromolecule itself, the symmetry of its binding isotherms and the underlying thermodynamic and mathematical relations, the role of symmetry in different allosteric models, and the effect of symmetry on the number of relaxation times shown by a macromolecule in its approach to equilibrium or a steady state. Finally there is the symmetry of the group of potentials and the resulting linkage relations which govern the response of the macromolecule to its ligands and embody the grammar of a macromolecular language.

Allosteric Site↗
PubMed1978

A macromolecular transducer as illustrated by trout hemoglobin IV.

Oxygen binding by trout Hb IV has been investigated as a function of pH up to 10 atmospheres (1 MPa) of pure O2. The results bring out an extreme proton-oxygen linkage, which gives rise to a Root effect. They are discussed in relation to the function of the hemoglobin as an oxygen pump. The system is of special interest as providing a prototype of a macromolecule acting as a transducer by coupling two allosterically linked reactions.

Allosteric Regulation↗
PubMed1977

Functional properties of partially oxidized trout hemoglobins.

This paper reports on a study of the effect of partial oxidation on oxygen and carbon monoxide binding by components I and IV of trout hemoglobin. The O2 binding equilibria of the various oxidation mixtures show a decrease in the heme-heme interactions as the number of oxidized sites is increased. However, the large Bohr effect, characteristic of Hb Trout IV, is maintained unchanged. Similarly the time course of CO combination changes on increasing the fractional oxidation, and the autocatalytic character of the CO binding kinetics is lost; however the pH dependence of the apparent "on" constant in the oxidation mixtures is similar to that characteristic of the native molecule. The results of the O2 equilibria and of CO binding kinetics may be interpreted in accordance with the two state concerted model suggesting that in the oxidation intermediates there is an increase in the fraction of the high affinity (R) conformation. Additional experiments on the effect of azide, and fluoride, ferric ligands which produce a change of spin state of the heme iron, suggest that additional second order conformational changes may also come into play.

Animals↗
PubMed1977

On the existence of a steady state in a biological system.

This paper deals with the existence, uniqueness, and stability of a critical point (steady state) in the case of a macromolecular system, such as an allosteric or polysteric protein, for which the first-order kinetic equations are nonlinear. It presents a brief outline of a rigorous proof (to be given in full elsewhere) that, in a restricted but not unrepresentative system of this kind, there always exists one and only one positive critical point and that this point is asymptotically stable in the large: no matter what its starting point, the system will always approach this point by some kind of relaxation process, however complex.

Kinetics↗
PubMed1975

Identification of chloride-binding sites in hemoglobin by nuclear-magnetic-resonance quadrupole-relaxation studies of hemoglobin digests.

35Cl minus-nuclear magnetic resonance (NMR) studies indicate that various digests of human hemoglobin with carboxypeptidase A and B, or a combination of the two, may be used for the identification of chloride binding sites. All the digestion products contain, like hemoglobin itself, at least two classes of binding sites, one of high, the others of low affinity. The pH dependence of the excess linewidth of the 35Cl minus NMR signal indicates that in the simple digests with either carboxypeptidase A or B, chloride is bound with high affinity at or near His-beta146-Asp-beta94 and at or near Val-alpha1-Arg-alpha141. The high-affinity sites show, in the case of the simple digests, a strong oxygen linkage which is lost in the forms digested with both carboxypeptidase A and B; this linkage may thus be correlated to the presence of conformational changes. Organic phosphates, like inositol hexaphosphate, show competition for some of the high-affinity chloride binding sites in hemoglobin and in the simple digests. This competition is likewise lost in the doubly digested hemoglobins.

Binding Sites↗
PubMed1975

The turning wheel: a study in steady states.

Subject to the limitation of one-step transitions, a system composed of a polyfunctional macromolecule (say a polyfunctional enzyme), present in fixed amount together with its ligands (substrates) in a fixed volume, can be represented by an r-dimensional cube of which each of the 2r corners corresponds to one of the microscopically different forms. In the steady state we may predict circulation of the macromolecule around the edges of the cube. This would provide a molecular mechanism whereby one enzymatic reaction could drive another, the enzyme itself acting as a transducer. Such a system is asymptotically stable and subject to a set of linkage relations derivable by the cofactor principle from the steady state equations.

Enzymes↗