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Daniel A Beard

Publications and source records attributed to Daniel A Beard.

8 recordsLinked to original sources
PubMed2004

Thermodynamic constraints for biochemical networks.

The constraint-based approach to analysis of biochemical systems has emerged as a useful tool for rational metabolic engineering. Flux balance analysis (FBA) is based on the constraint of mass conservation; energy balance analysis (EBA) is based on non-equilibrium thermodynamics. The power of these approaches lies in the fact that the constraints are based on physical laws, and do not make use of unknown parameters. Here, we show that the network structure (i.e. the stoichiometric matrix) alone provides a system of constraints on the fluxes in a biochemical network which are feasible according to both mass balance and the laws of thermodynamics. A realistic example shows that these constraints can be sufficient for deriving unambiguous, biologically meaningful results. The thermodynamic constraints are obtained by comparing of the sign pattern of the flux vector to the sign patterns of the cycles of the internal cycle space via connection between stoichiometric network theory (SNT) and the mathematical theory of oriented matroids.

Energy Metabolism↗
PubMed2003

Myocardial oxygenation in isolated hearts predicted by an anatomically realistic microvascular transport model.

An anatomically realistic model for oxygen transport in cardiac tissue is introduced for analyzing data measured from isolated perfused guinea pig hearts. The model is constructed to match the microvascular anatomy of cardiac tissue based on available morphometric data. Transport in the three-dimensional system (divided into distinct microvascular, interstitial, and parenchymal spaces) is simulated. The model is used to interpret experimental data on mean cardiac tissue myoglobin saturation and to reveal differences in tissue oxygenation between buffer-perfused and red blood cell-perfused isolated hearts. Interpretation of measured mean myoglobin saturation is strongly dependent on the oxygen content of the perfusate (e.g., red blood cell-containing vs. cell-free perfusate). Model calculations match experimental values of mean tissue myoglobin saturation, measured mean myoglobin, and venous oxygen tension and can be used to predict distributions of intracellular oxygen tension. Calculations reveal that approximately 20% of the tissue is hypoxic with an oxygen tension of <0.5 mmHg when the buffer is equilibrated with 95% oxygen to give an arterial oxygen tension of over 600 mmHg. The addition of red blood cells to give a hematocrit of only 5% prevents tissue hypoxia. It is incorrect to assume that the usual buffer-perfused Langendorff heart preparation is adequately oxygenated for flows in the range of < or =10 ml. min-1. ml tissue-1.

Animals↗
PubMed2003

Comparison of buffer and red blood cell perfusion of guinea pig heart oxygenation.

Myocardial mean myoglobin oxygen saturation was determined spectroscopically from isolated guinea pig hearts perfused with red blood cells during increasing hypoxia. These experiments were undertaken to compare intracellular myoglobin oxygen saturation in isolated hearts perfused with a modest concentration of red blood cells (5% hematocrit) with intracellular myoglobin saturation previously reported from traditional buffer-perfused hearts. Studies were performed at 37 degrees C with hearts paced at 240 beats/min and a constant perfusion pressure of 80 cmH2O. It was found that during perfusion with a hematocrit of 5%, baseline mean myoglobin saturation was 93% compared with 72% during buffer perfusion. Mean myoglobin saturation, ventricular function, and oxygen consumption remained fairly constant for arterial perfusate oxygen tensions above 100 mmHg and then decreased precipitously below 100 mmHg. In contrast, mean myoglobin saturation, ventricular function, and oxygen consumption began to decrease even at high oxygen tension with buffer perfusion. The present results demonstrate that perfusion with 5% red blood cells in the perfusate increases the baseline mean myoglobin saturation and better preserves cardiac function at low oxygen tension relative to buffer perfusion. These results suggest that caution should be used in extrapolating intracellular oxygen dynamics from buffer-perfused to blood-perfused hearts.

Animals↗
PubMed2003

Constructing irregular surfaces to enclose macromolecular complexes for mesoscale modeling using the discrete surface charge optimization (DISCO) algorithm.

Salt-mediated electrostatics interactions play an essential role in biomolecular structures and dynamics. Because macromolecular systems modeled at atomic resolution contain thousands of solute atoms, the electrostatic computations constitute an expensive part of the force and energy calculations. Implicit solvent models are one way to simplify the model and associated calculations, but they are generally used in combination with standard atomic models for the solute. To approximate electrostatics interactions in models on the polymer level (e.g., supercoiled DNA) that are simulated over long times (e.g., milliseconds) using Brownian dynamics, Beard and Schlick have developed the DiSCO (Discrete Surface Charge Optimization) algorithm. DiSCO represents a macromolecular complex by a few hundred discrete charges on a surface enclosing the system modeled by the Debye-Hückel (screened Coulombic) approximation to the Poisson-Boltzmann equation, and treats the salt solution as continuum solvation. DiSCO can represent the nucleosome core particle (>12,000 atoms), for example, by 353 discrete surface charges distributed on the surfaces of a large disk for the nucleosome core particle and a slender cylinder for the histone tail; the charges are optimized with respect to the Poisson-Boltzmann solution for the electric field, yielding a approximately 5.5% residual. Because regular surfaces enclosing macromolecules are not sufficiently general and may be suboptimal for certain systems, we develop a general method to construct irregular models tailored to the geometry of macromolecules. We also compare charge optimization based on both the electric field and electrostatic potential refinement. Results indicate that irregular surfaces can lead to a more accurate approximation (lower residuals), and the refinement in terms of the electric field is more robust. We also show that surface smoothing for irregular models is important, that the charge optimization (by the TNPACK minimizer) is efficient and does not depend on the initial assigned values, and that the residual is acceptable when the distance to the model surface is close to, or larger than, the Debye length. We illustrate applications of DiSCO's model-building procedure to chromatin folding and supercoiled DNA bound to Hin and Fis proteins. DiSCO is generally applicable to other interesting macromolecular systems for which mesoscale models are appropriate, to yield a resolution between the all-atom representative and the polymer level.

Algorithms↗
PubMed2003

Unbiased rotational moves for rigid-body dynamics.

We introduce an unbiased protocol for performing rotational moves in rigid-body dynamics simulations. This approach-based on the analytic solution for the rotational equations of motion for an orthogonal coordinate system at constant angular velocity-removes deficiencies that have been largely ignored in Brownian dynamics simulations, namely errors for finite rotations that result from applying the noncommuting rotational matrices in an arbitrary order. Our algorithm should thus replace standard approaches to rotate local coordinate frames in Langevin and Brownian dynamics simulations.

Algorithms↗
PubMed2003

Stoichiometric network theory for nonequilibrium biochemical systems.

We introduce the basic concepts and develop a theory for nonequilibrium steady-state biochemical systems applicable to analyzing large-scale complex isothermal reaction networks. In terms of the stoichiometric matrix, we demonstrate both Kirchhoff's flux law sigma(l)J(l)=0 over a biochemical species, and potential law sigma(l) mu(l)=0 over a reaction loop. They reflect mass and energy conservation, respectively. For each reaction, its steady-state flux J can be decomposed into forward and backward one-way fluxes J = J+ - J-, with chemical potential difference deltamu = RT ln(J-/J+). The product -Jdeltamu gives the isothermal heat dissipation rate, which is necessarily non-negative according to the second law of thermodynamics. The stoichiometric network theory (SNT) embodies all of the relevant fundamental physics. Knowing J and deltamu of a biochemical reaction, a conductance can be computed which directly reflects the level of gene expression for the particular enzyme. For sufficiently small flux a linear relationship between J and deltamu can be established as the linear flux-force relation in irreversible thermodynamics, analogous to Ohm's law in electrical circuits.

Animals↗
PubMed2002

Energy balance for analysis of complex metabolic networks.

Predicting behavior of large-scale biochemical networks represents one of the greatest challenges of bioinformatics and computational biology. Computational tools for predicting fluxes in biochemical networks are applied in the fields of integrated and systems biology, bioinformatics, and genomics, and to aid in drug discovery and identification of potential drug targets. Approaches, such as flux balance analysis (FBA), that account for the known stoichiometry of the reaction network while avoiding implementation of detailed reaction kinetics are promising tools for the analysis of large complex networks. Here we introduce energy balance analysis (EBA)--the theory and methodology for enforcing the laws of thermodynamics in such simulations--making the results more physically realistic and revealing greater insight into the regulatory and control mechanisms operating in complex large-scale systems. We show that EBA eliminates thermodynamically infeasible results associated with FBA.

Biophysics↗