Abstracts of Articles in 1972 - 1979

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  1. Acute Metabolic Responses in Myxedema to Large Doses of Intravenous L-Thyroxine.
  2. Apparent Cooperativity in Radioimmunoassay of Human Chorionic Gonadotropin.
  3. A Study of the Distances Obtained from Nuclear Magnetic Resonance Nuclear Overhauser Effect and Relaxation Time Measurements in Organic Structure Determination. Distances Involving Internally Rotating Methyl Groups. Application to cis- and trans-Crotonaldehyde.
  4. "Semiempirical" Models for Biomembrane Phase Transitions and Phase Separations.
  5. Low Values of the Scheraga-Mandelkern β Parameter for Proteins. An Explanation Based on Porous Sphere Hydrodynamics.
  6. Frictional Properties of Multisubunit Structures.
  7. Frictional Properties of Nonspherical Multisubunit Structures. Application to Tubules and Cylinders.
  8. The Hinge-Bending Mode in Lysozyme.
  9. Hydrodynamic Effect on the Coagulation of Porous Biopolymers.
  10. Nonsteady Hydrodynamics of Biopolymer Motions.
  11. Molecular Dynamics Study of the Bovine Pancreatic Trypsin Inhibitor.
  12. Dynamics of Folded Proteins.
  13. Internal Motions of Antibody Molecules.
  14. Brownian Dynamics with Hydrodynamic Interactions.
  15. Protein Structural Fluctuations During a Period of 100 ps.
  16. Picosecond Dynamics of Tyrosine Side Chains in Proteins.
  17. Dynamics of Activated Processes in Globular Proteins.
  18. Diffusive Langevin Dynamics of Model Alkanes.

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Acute Metabolic Responses in Myxedema to Large Doses of Intravenous L-Thyroxine

E.C. Ridgeway, J.A. McCammon, J. Benotti, F. Maloof

Annals of Internal Medicine, Vol. 77, No. 4, pp. 549-555 (1972)

[PubMed: 4642735]


Apparent Cooperativity in Radioimmunoassay of Human Chorionic Gonadotropin

B.D. Weintraub, S.W. Rosen, J.A. McCammon, R.L. Perlman

Endocrinology, Vol. 92, Issue 4, pp. 1250-1255 (1973)

[PubMed: 4734434]


A Study of the Distances Obtained from Nuclear Magnetic Resonance Nuclear Overhauser Effect and Relaxation Time Measurements in Organic Structure Determination. Distances Involving Internally Rotating Methyl Groups. Application to cis- and trans-Crotonaldehyde

R. Rowan III, J.A. McCammon, B.D. Sykes

Journal of the American Chemical Society, Vol. 96, No. 15, pp. 4773-4780 (1974)

Absolute internuclear distances between all of the protons of cis- and trans-crotonaldehyde in solution have been obtained by measuring the 1H{1H} nuclear Overhauser enhancements between all of the spins and the 1H and 1 3C nuclear spin-lattice relaxation times for all of the spins. The results are compared with the reported microwave structure for trans-crotonaldehyde and a theoretically optimized structure (starting from the X-ray structure) for cis-crotonaldehyde. The internuclear distances involving the methyl protons are used to test two models for the effectivep osition of the methyl protons when internal motions are considered.

"Semiempirical" Models for Biomembrane Phase Transitions and Phase Separations

J.A. McCammon, J.M. Deutch

Journal of the American Chemical Society, Vol. 97, No. 23, pp. 6675-6681 (1975)

[PubMed: 1184878]

Experimental studies are reviewed to construct a model for the hydrocarbon chain disordering in "fluid" phospholipid bilayers. Together with approximate expressions for the interactions between neighboring molecules, this information is used to construct a simple statistical thermodynamic theory of the chain "melting" based on the Bragg-Williams approximation. Two unknown parameters in the theory, the interaction between neighboring chains in the "fluid" state and the change in head group interaction associated with the chain "melting", are determined for particular classes of phospholipids by reference to experimental data. The theory is applied to predict the "melting" temperatures of single-component bilayers and the phase diagrams of two-component bilayers. Possible extensions of this type of theory to rationalize other phenomena observed in biological membranes are discussed.

Low Values of the Scheraga-Mandelkern β Parameter for Proteins. An Explanation Based on Porous Sphere Hydrodynamics

J.A. McCammon, J.M. Deutch, Victor A. Bloomfield

Biopolymers, Vol. 14, Issue 12, pp. 2479-2487 (1975)

Several globular proteins have values of the Scheraga-Mandelkern β parameter significantly below the theoretical minimum value, β0 = 2.112 × 106, for an impermeable sphere. Using the Felderhof-Deutch generalization of the Debye-Bueche-Brinkman theory of hydrodynamics of porous spheres, we have shown that values of β slightly below this supposed minimum are theoretically expected. A porous sphere of uniform density has a minimum β of 2.084 × 106 at a Debye shielding ratio of 6.5, corresponding, for example, to a sphere radius of 11 Å and an inverse hydrodynamic shielding length of 0.6 Å-1, values not far from those of small proteins. A two-layer porous sphere model gives similar results. Although this is the first theoretical explanation of values of β below β0, the theory is incomplete since β values as low as 2.03 × 106 are observed.

Frictional Properties of Multisubunit Structures

J.A. McCammon, J.M. Deutch, B.U. Felderhof

Biopolymers, Vol. 14, Issue 12, pp. 2613-2623 (1975)

The translational drag, rotational drag, and intrinsic viscosity of spherical multisubunit structures have been calculated analytically using the Felderhof-Deutch theory of polymer frictional properties. The structures considered were hollow shells, spheres with uniform subunit density, and spheres covered with a subunit layer of different density. Changes in the transport coefficients resulting from the random removal of subunits and from the variation of subunit size are calculated. For the case of the shell, the results agree with the numerical computations of Bloomfield, Dalton, and Van Holde [Biopolymers 5, 135, 149 (1967)].

Frictional Properties of Nonspherical Multisubunit Structures. Application to Tubules and Cylinders

J.A. McCammon, J.M. Deutch

Biopolymers, Vol. 15, Issue 7, pp. 1397-1408 (1976)

[PubMed: 949541]

Methods are described for numerical calculation of the anisotropic components of the translational and rotational friction coefficient tensors and of the intrinsic viscosity for rigid multisubunit structures in dilute solution. The methods apply to assemblies of any shape, provided that translation-rotation coupling is negligible.

Application is made to short cylindrical and tubular structures. Anomalous results arise when the Oseen tensor is used to describe the hydrodynamic interaction of the subunits, but these are corrected by use of a modified tensor. Transport coefficients for hollow tubules with typical supramolecular dimensions are found to be nearly the same as those for the corresponding solid cylinders. The Scheraga-Mandelkern equation is found to be useful for the determination of the molecular weights of such structures. For long hollow structures such as microtubules, use of the corresponding solid cylinder or wormlike chain equations should be adequate for interpreting hydrodynamic studies.

The Hinge-Bending Mode in Lysozyme

J. Andrew McCammon, Bruce R. Gelin, Martin Karplus, Peter G. Wolynes

Nature, Vol. 262, No. 5566, pp. 325-326 (1976)

[PubMed: 958384]

A complete description of an enzyme requires a knowledge of its structure and the dynamics of its function. From the crystal structures of enzymes and enzyme-inhibitor complexes and the known chemistry of model systems, it has been possible in some cases to draw reasonable inferences concerning the mechanisms of enzyme-catalysed reactions. Little has been done so far, however, to supplement such essentially static results by an investigation of the reaction dynamics. This requires an understanding of the internal motions of the enzyme, as well as those of the substrate, since both are likely to be essential to the function. Here we present a theoretical study of a low frequency vibration involving the two globular lobes of lysozyme between which the cleft containing the active site is located. Any motion involving this cleft could play a part in the catalytic activity; in fact, atom displacements of up to 0.75 Å found in a comparison of the free enzyme and the enzyme-inhibitor complex indicate that the cleft has closed down in the latter. The force constant for the low frequency bending vibration corresponding to the opening and closing of the cleft is obtained from empirical energy functions. Because the protein surface moves appreciably during the vibration, damping effects resulting from the viscous dissipation in the solvent are included in the calculation.

Hydrodynamic Effect on the Coagulation of Porous Biopolymers

Peter G. Wolynes, J.A. McCammon

Macromolecules, Vol. 10, No. 1, pp. 86-87 (1977)

The rate of diffusional coagulation of globular macromolecules vanishes in hydrodynamic calculations which employ stick boundary conditions at the solvent-macromolecule surface. We show that finite coagulation rates are predicted by a theory which recognizes the porous or rough character of polymer surfaces. Approximate rates for the coagulation of neutral proteins are calculated. The theory is relevant to other macromolecular rate processes, such as large-scale internal motions in proteins.

Nonsteady Hydrodynamics of Biopolymer Motions

J.A. McCammon, Peter G. Wolynes

Journal of Chemical Physics, Vol. 66, Issue 4, pp. 1452-1456 (1977)

Many biopolymers undergo conformational fluctuations in which large subunits move relative to each other under the influence of significant mechanical restoring forces. It is shown that nonsteady hydrodynamic effects may be important in the solvent response to such macromolecular motions. This result is in marked contrast to the familiar case of conformational fluctuations of random coil polymers, which move under the influence of weak entropic forces. The nonsteady solvent response is shown to affect the details of the biopolymer motion and to produce special qualitative features in the Raman light scattering spectrum of such macromolecules.

Molecular Dynamics Study of the Bovine Pancreatic Trypsin Inhibitor

J.A. McCammon

In "Report of the 1976 Workshop, Models for Protein Dynamics," H.J.C. Berendsen, Ed., Centre Europeen de Calcul Atomique et Moleculaire, Universite de Paris IX, France, pp. 137-152 (1977)


Dynamics of Folded Proteins

J. Andrew McCammon, Bruce R. Gelin, Martin Karplus

Nature, Vol. 267, No. 5612, pp. 585-590 (1977)

[PubMed: 301613]

The dynamics of a folded globular protein (bovine pancreatic trypsin inhibitor) have been studied by solving the equations of motion for the atoms with an empirical potential energy function. The results provide the magnitude, correlations and decay of fluctuations about the average structure. These suggest that the protein interior is fluid-like in that the local atom motions have a diffusional character.

Internal Motions of Antibody Molecules

J.A. McCammon, M. Karplus

Nature, Vol. 268, No. 5622, pp. 765-766 (1977)

[PubMed: 895880]

Antibody molecules of the IgG class are composed of three covalently linked regions. Two of these (designated Fab) are identical and bind antigen; the third (Fc) has been identified as the site of antibody effector functions (for example, complement fixation), which are activated by antigen binding. There is evidence that the binding of antigen to the Fab region induces an allosteric transition in IgG and that this transition may be a step in the effector activation process. The findings of Pecht et al. indicate that for complement fixation both Fab regions must bind antigen, even though binding to one induces some conformational change in Fc. Binding of hapten does not lead to complement fixation in general, but some exceptions to this rule are known. The interchain disulphide bridges must be intact for Fab ligand binding to have a productive effect on the Fc region. Both the Fab and Fc regions have a domain structure; each consists of a pair of compact lobes covalently linked by strands of polypeptide chains. A schematic diagram of the connectivity of the IgG lobes is given by Padlan. One of the fundamental questions involved in antibody function is the nature of the mechanism by which binding of antigen to the Fab regions affects the Fc region. Huber et al. have recently outlined a possible allosteric model for the activation step on the basis of X-ray and other data. In this note we use simple diffusion arguments to estimate the characteristic times associated with the Huber proposal. Since the analysis deals only with the relative motion of the IgG domains, it is possible that slower intradomain structural changes are also involved in the activation process; if so, the estimated characteristic times would be lower bounds for the activation time. The role of conformational transitions in effector function activation is still in dispute, but we note that the diffusional model may be useful for analysing other dynamical phenomena in immunoglobulins, such as their fluorescence depolarisation behaviour.

Brownian Dynamics with Hydrodynamic Interactions

Donald L. Ermak, J.A. McCammon

Journal of Chemical Physics, Vol. 69, Issue 4, pp. 1352-1360 (1978)

A method for simulating the Brownian dynamics of N particles with the inclusion of hydrodynamic interactions is described. The particles may also be subject to the usual interparticle or external forces (e.g., electrostatic) which have been included in previous methods for simulating Brownian dynamics of particles in the absence of hydrodynamic interactions. The present method is derived from the Langevin equations for the N particle assembly, and the results are shown to be consistent with the corresponding Fokker-Planck results. Sample calculations on small systems illustrate the importance of including hydrodynamic interactions in Brownian dynamics simulations. The method should be useful for simulation studies of diffusion limited reactions, polymer dynamics, protein folding, particle coagulation, and other phenomena in solution.

Protein Structural Fluctuations During a Period of 100 ps

M. Karplus, J.A. McCammon

Nature, Vol. 277, No. 5697, p. 578 (1979)

[PubMed: 763343]

A recent 9-ps molecular dynamics simulation of the bovine pancreatic trypsin inhibitor (PTI) at 295 K revealed a rich variety of motional phenomena at the atomic level on a picosecond time scale. To obtain information about longer time processes, and to characterise more accurately the short time results, a 96-ps dynamical simulation of PTI at an average temperature of 306 K has been completed with the techniques used previously; an extended equilibration period of 72 ps before simulation served to eliminate internal stresses. Analysis of the present simulation has confirmed most of the conclusions of the earlier study but has shown in addition that there are significant features of the dynamics that can be observed only over a longer period, ~ 100 ps.

Picosecond Dynamics of Tyrosine Side Chains in Proteins

J. Andrew McCammon, Peter G. Wolynes, Martin Karplus

Biochemistry, Vol. 18, No. 6, pp. 927-942 (1979)

[PubMed: 427100]

To probe the details of small amplitude motions in proteins, a dynamical analysis of the orientation fluctuations of two tyrosine side chains in the bovine pancreatic trypsin inhibitor is presented. Detailed results are given for the time history and correlation functions obtained for the ring motion from a molecular dynamics simulation of the entire protein. It is shown that even on a picosecond time scale orientational fluctuations of +/-30° from the average position occur for the tyrosine rings in the interior of the protein. It is found that the Langevin equation is applicable to the ring torsional motion, which corresponds to that of an angular harmonic oscillator with near-critical damping. Two possible microscopic models for the observed damping effects are outlined. One of these, analogous to liquid behavior, is based on kinetic theory and takes account of the collisions which occur between atoms of the protein; the other, more analogous to solid behavior, involves the coupling among a large number of harmonic oscillators. The collisional model with parameters obtained from theoretical estimates leads to good agreement with the correlation functions from the dynamic simulation. However, the dephasing of harmonic oscillations can yield similar short-time results so that a distinction between the two models is difficult. The importance of damping effects on the motions involved in conformational transitions and enzymatic reactions is discussed.

Dynamics of Activated Processes in Globular Proteins

J.A. McCammon, M. Karplus

Proceedings of the National Academy of Sciences of the USA, Vol. 76, No. 8, pp. 3585-3589 (1979)

[PubMed: 291026]

A procedure for the dynamical simulation of activated processes, such as ligand binding and enzymatic reactions, in a globular protein is outlined. Preliminary calculations of the transition state geometry and barrier crossing trajectories are presented for a model reaction, the rotation of an aromatic ring in the bovine pancreatic trypsin inhibitor. The results show that repulsive nonbonded interactions between the ring atoms and the atoms in the surrounding protein matrix determine the dynamical character of the reorientation process; the nonbonded interactions are the source of the rotational barrier and of the impulses that speed up or slow down the ring motion during the barrier crossings.

Diffusive Langevin Dynamics of Model Alkanes

Ronald M. Levy, Martin Karplus, J. Andrew McCammon

Chemical Physics Letters, Vol. 65, Issue 1, pp. 4-11 (1979).

The diffusive Langevin equation of motion is used to simulate the equilibrium for times up to 100 ns. Comparisons are made between the results obtained with an isolated molecule potential surface and with one modified to incorporate solvent effects.

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