Search Results - (Author, Cooperation:J. A. McCammon)

2013-12-24

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Acyl Carrier Protein/*chemistry/*metabolism ; Binding Sites ; Catalytic Domain ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Fatty Acid Synthase, Type II/chemistry/metabolism ; Fatty Acids/*biosynthesis ; Histidine/metabolism ; Hydro-Lyases/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Binding ; Protein Interaction Maps

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

The evaluation of free energy differences using the perturbation method or thermodynamic integration method requires special caution if multiple rotational isomeric states may exist in the system under investigation. In this article a recently suggested procedure to properly treat rotational isomeric states is illustrated with a molecular dynamics simulation of an aqueous solution of uncomplexed 18-crown-6 crown ether, as an example of a system in which large numbers of isomeric states may exist. By using very long molecular dynamics simulations, thermodynamic perturbation methods and symmetry arguments, the free energy of host organization into the conformation required to form the complex with K+ is estimated to be 2.6 kJ mol−1. It has also been found that the lowest energy conformations of 18-crown-6 in vacuo do not necessarily correspond to the most populated conformations in aqueous solution.

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1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

A modified thermodynamic integration technique is presented to obtain free energy differences from molecular dynamics simulations. In this multiconfiguration thermodynamic integration technique, the commonly employed single configuration (slow growth) approximation is not made. It is shown, by analysis of the sources of error, how the multiconfiguration variant of thermodynamic integration allows for a soundly based assessment of the statistical error in the evaluated free energy difference. Since ensembles of configurations are generated for each integration step, a statistical error can be evaluated for each integration step. By generating ensembles of different lengths, the statistical error can be equally distributed over the integration. This eliminates the difficult problem in single configuration thermodynamic integrations of determining the best rate of change of the Hamiltonian, which is usually based on equally distributing the free energy change. At the same time, this procedure leads to a more efficient use of computer time by providing the possibility of added accuracy from separate calculations of the same Hamiltonian change. The technique is applied to a simple but illustrative model system consisting of a monatomic solute in aqueous solution. In a second example, a combination of multiconfiguration thermodynamic integration and thermodynamic perturbation is used to obtain the potentials of mean force for rotation of the sidechain dihedral angles for valine and threonine dipeptides with restrained backbones in aqueous solution.

Electronic Resource

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

Using 1,2-dimethoxy ethane in aqueous solution as an example, the applicability of the perturbation method and the thermodynamic integration technique to evaluate free energy differences is considered for systems with multiple rotational isomeric states. It is shown that the naive application of these methods to evaluate free energy differences for such systems, even in a simple case such as the free energy of hydration of 1,2-dimethoxy ethane, may lead to unreasonable results. This problem is due to the fact that, in a conventional simulation, it is unlikely that all isomeric states will be sampled with the appropriate equilibrium probabilities. A procedure is proposed to estimate the contributions of isomeric states in free energy difference calculations.

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1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

The effects of co- and counterion dynamics on the rates of diffusion controlled reactions are investigated. A model system consisting of univalent soft spheres in a uniform dielectric medium is simulated by the Brownian dynamics method. This system is used to study the effects of ionic atmosphere dynamics on the rate of recombination of an ion pair. The results show a small (2%) increase in the rate compared to the traditional Debye–Hückel description. A parallel calculation where the atmospheric ions are frozen in equilibrium configurations around the target (unperturbed by the incoming reactant) yields results which are very close to the Debye–Hückel results. Larger nonequilibrium effects are expected for multivalent electrolytes.

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1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

A technique is described to determine umbrella biasing potentials that can be used to enhance sampling of rotational isomeric states in molecular simulations of polypeptides in water. The analytical biasing potential functions are obtained through fitting of potentials of mean force obtained by thermodynamic integration simulations to a small number of functions used to describe dihedral torsion. The resulting dramatic increase in efficiency of sampling is illustrated by comparison of molecular simulations of the alanine–dipeptide molecule in aqueous solution, with and without the use of the biasing potentials. The same biasing potentials were used in simulations of the alanine–tripeptide and the alanine–heptapeptide in aqueous solution. Similar dramatic increases in sampling efficiency were observed for these simulations, when the biasing potentials were applied, which suggests that these biasing potentials, although determined for the dipeptide, may be transferable to larger peptide chains. It is illustrated how the biasing potentials can be used in biasing potential annealing simulations, leading to rapid folding of peptide chains into aqueous solution structures with low energy.

Electronic Resource

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

A new method of simultaneously scaling and shifting the Lennard-Jones (LJ) potential in molecular dynamics (MD) and thermodynamic integration (TI) simulations is presented. The approach allows the smooth creation or annihilation of atoms or molecules in an ensemble of solvent molecules during a molecular simulation. By scaling and shifting the LJ potential in the direction of the interatomic distance between particles, the method eliminates the problem of the creation or annihilation of a large repulsive LJ potential at the initial or final state of a TI. The optimal degree of shifting and scaling the LJ potential as a function of a control variable λ was studied for the annihilation and creation of neon in aqueous solution. The method was further tested on the calculation of the free energy of aqueous solvation of a small molecule, ethanol. In contrast to linear scaling of the LJ potential during TI, the calculated free energies using the new separation-shifted scaling approach are reasonably well converged after 200–500 ps of simulation and show smaller hysteresis comparing forward and reverse TI.

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1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

The Brownian dynamics simulation method of Northrup et al. is extended so that dynamical trajectories can be initiated with the reactants in close proximity to one another. A more general analysis is presented which shows that this procedure is exact in cases where the first-time encounter flux to the more proximal starting surface is isotropic, such as cases where interparticle forces are centrosymmetric, but is approximate otherwise. Diffusion controlled rate constants for three model systems obtained by this procedure are compared with analytic results or with exact rate constants derived from simulations following the original Northrup procedure. Agreement is good to excellent in all cases considered. The extended method is expected to be of considerable practical importance in systems with highly anisotropic reactivity where it is computationally inefficient to obtain rate constants by the original method.

Electronic Resource

1089-7690

AIP Digital Archive

Physics

Chemistry and Pharmacology

We propose a theory for the influence of conformational dynamics of solvated macromolecules on the translational self-correlation functions and associated laser light scattering spectra of the solution in an external electric field. This theory assumes that the electrophoretic drift velocity of a macroion may be coupled to its internal degrees of freedom via an unspecified auxiliary stochastic process to which we refer as "electrophoretic mobility fluctuations.'' A surprisingly diverse set of fluctuation-generated spectral signatures, which depend strongly on the underlying statistical model, emerge from the analysis. These effects range from skewed Lorentzian profiles to satellite lines having a field-dependent amplitude.

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1476-4687

Nature Archives 1869 - 2009

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

[Auszug] An overall measure of the correspondence between the time-average dynamical and X-ray structures2 is given by the radius of gyration. It equals 10.22 A (with fluctuations of ±0.1 A) for the former and 10.96 A for the latter. The primary source of difference between the two are the positions ...

Electronic Resource

1476-4687

Nature Archives 1869 - 2009

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

[Auszug] Huber et al.9 assume that the lobes have relatively little interaction with each other in the unliganded IgG. Thus, neighbouring lobes are free to rotate relative to each other over certain angular ranges. Inspection of the Fab regions in the IgG structure suggests that the VL-VH dimer (the ...

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

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.

2 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

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)].

2 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

Multiconfiguration thermodynamic integration was used to determine the relative binding strength of tacrine and 6-chlorotacrine by Torpedo californica acetylcholinesterase. 6-Chlorotacrine appears to be bound stronger by 0.7 ± 0.4 kcal/mol than unsubstituted tacrine when the active site triad residue His-440 is deprotonated. This result is in excellent agreement with experimental inhibition data on electric eel acetylcholinesterase. Electrostatic Poisson-Boltzmann calculations confirm that order of binding strength, resulting in ΔG of binding of -2.9 and -3.3 kcal/mol for tacrine and chlorotacrine, respectively, and suggest inhibitor binding does not occur when His-440 is charged. Our results suggest that electron density redistribution upon tacrine chlorination is mainly responsible for the increased attraction potential between protonated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84. © 1996 John Wiley & Sons, Inc.

4 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

A simplified model of a polypeptide chain is described. Each residue is represented by a single interaction center. The energy of the chain and the force acting on each residue are given as a function of the residue coordinates. Terms to approximate the effect of solvent and the stabilization energy of helix formation are included. The model is used to study equilibrium and dynamical aspects of the helix-coil transition. The equilibrium properties examined include helix-coil equilibrium constants and their dependence on chain position. Dynamical properties are examined by a stochastic simulation of the Brownian motion of the chain in its solvent surroundings. Correlations in the motions of the residues are found to have an important influence on the helix-coil transition rates.

5 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

A quasi-harmonic approximation is described for studying very low frequency vibrations and flexible paths in proteins. The force constants of the empirical potential function are quadratic approximations to the potentials of mean force; they are evaluated from a molecular dynamics simulation of a protein based on a detailed anharmonic potential. The method is used to identify very low frequency (∼1 cm-1) normal modes for the protein pancreatic trypsin inhibitor. A simplified model for the protein is used, for which each residue is represented by a single interaction center. The quasi-harmonic force constants of the virtual internal coordinates are evaluated and the normal-mode frequencies and eigenvectors are obtained. Conformations corresponding to distortions along selected low-frequency modes are analyzed.

5 Ill.

Electronic Resource

0020-7608

Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

An approximate valence bond (AVB) method was parametrized at a microscopic level for proton transfer and hydroxyanion nucleophilic reactions in enzyme catalytic processes. The method was applied to describe hydrolytic activity of phospholipase A2. The AVB parametrization is based on density functional and conventional ab initio calculations calibrated with respect to experimental data in the gas phase. The method was used as a fast generator of the potential energy function in a quantum-classical molecular dynamics (QCMD) simulations describing atomic motions as well as propagation of the proton wave function in the enzyme active site. The protein environment surrounding the active site and solvent effects are included in the model via electrostatic interactions perturbing the original AVB Hamiltonian. © 1996 John Wiley & Sons, Inc.

17 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

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.

6 Ill.

Electronic Resource

0006-3525

Chemistry ; Polymer and Materials Science

Wiley InterScience Backfile Collection 1832-2000

Chemistry and Pharmacology

The method of Ermak and McCammon [Ermak, D. L. & McCammon, J. A. (1978) J. Chem. Phys. 69, 1352-1360] is used to simulate the Brownian dynamics of a system of identical, interacting beads. In the present study, we use the method to obtain transport coefficients for a variety of rigid and flexible structures modeled as arrays of spherical subunits. Constraints are enforced using the SHAKE algorithm or a modification, SHAKE-HI, that is described for the first time. In SHAKE-HI, hydrodynamic interactions between subunits are taken into account when the constraints are enforced. Use of SHAKE-HI yields transport coefficients that are in perfect agreement with those obtained by other methods. The primary advantage of the present method is its generality. We also propose that multistep Brownian dynamics may be important in simulating actual experiments (such as fluorescence depolarization) on well-defined model systems that possess an arbitrary degree of internal flexibility.

5 Ill.

Electronic Resource