arXiv subjects

Daniel A. Beard

Publications and source records attributed to Daniel A. Beard.

10 recordsLinked to original sources

arXiv2019

Universal Relation Between Thermodynamic Driving Force and One-Way Fluxes in a Nonequilibrium Chemical Reaction with Complex Mechanism

In nonequilibrium chemical reaction systems, a fundamental relationship between unbalanced kinetic one-way fluxes and thermodynamic chemical driving forces is believed to exists. However this relation has been rigorously demonstrated only in a few cases in which one-way fluxes are well defined. In terms of its stochastic kinetic representation, we formulate the one-way fluxes for a general chemical reaction far from equilibrium, with arbitrary complex mechanisms, multiple intermediates, and internal kinetic cycles. For each kinetic cycle, the logarithm of the ratio of the steady-state forward and backward one-way fluxes is equal to the free energy difference between the reactants and products along the cycle. This fundamental relation is further established for general chemical reaction networks with multiple input and output complexes. Our result not only provides an equivalent definition of free energy difference in nonequilibrium chemical reaction networks, it also unifies the stochastic and macroscopic nonequilibrium chemical thermodynamics in a very broad sense.

physics.chem-ph↗

arXiv2013

The Inferred Cardiogenic Gene Regulatory Network in the Mammalian Heart

Cardiac development is complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. The algorithm generates many different putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of topologies are merged and filtered to generate a scale-free, hierarchical network. The network is validated with known gene interactions and used to identify regulatory pathways critical to the developing mammalian heart. The predicted gene interactions are prioritized using semantic similarity and gene profile uniqueness metrics. Using these metrics, the network is expanded to include all known mouse genes to form the most likely cardiogenic gene regulatory network. The method outlined herein provides an informative approach to network inference and leads to clear testable hypotheses related to gene regulation.

q-bio.MN↗

arXiv2013

Arterial stiffening provides sufficient explanation for primary hypertension

Hypertension is one of the most common age-related chronic diseases and by predisposing individuals for heart failure, stroke and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age, and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure, arise as emergent properties of the integrated system. Results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function. The results support the view that a major target for treating chronic hypertension in the elderly is the reestablishment of a proper baroreflex response.

q-bio.TO↗

arXiv2013

A Biophysical Model of the Mitochondrial ATP-Mg/Pi Carrier

Mitochondrial adenine nucleotide (AdN) content is regulated through the Ca2+-activated, electroneutral ATP-Mg/Pi carrier (APC). The APC is a protein in the mitochondrial carrier super family that localizes to the inner mitochondrial membrane (IMM). It is known to modulate a number of processes that depend on mitochondrial AdN content, such as gluconeogenesis, protein synthesis, and citrulline synthesis. Despite this critical role, a kinetic model of the underlying mechanism has not been developed and validated. Here, a biophysical model of the APC is developed that is thermodynamically balanced and accurately reproduces a number of reported data sets from isolated rat liver and rat kidney mitochondria. The model is based on an ordered bi-bi mechanism for hetero-exchange of ATP and Pi and also includes homo-exchanges of ATP and Pi to explain both the initial rate and time course data on ATP and Pi transport via the APC. The model invokes seven kinetic parameters regarding the APC mechanism and three parameters related to matrix pH regulation by external Pi. These parameters are estimated based on nineteen independent data curves; the estimated parameters are validated using six additional data curves. The model takes into account the effects of pH, Mg2+ and Ca2+ on ATP and Pi transport via the APC and supports the conclusion that the pH gradient across the IMM serves as the primary driving force for AdN uptake or efflux. Moreover, computer simulations demonstrate that extra-matrix Ca2+ modulates the turnover rate of the APC and not the binding affinity of ATP, as previously suggested.

q-bio.CB↗

arXiv2012

Specification, Construction, and Exact Reduction of State Transition System Models of Biochemical Processes

Biochemical reaction systems may be viewed as discrete event processes characterized by a number of states and state transitions. These systems may be modeled as state transition systems with transitions representing individual reaction events. Since they often involve a large number of interactions, it can be difficult to construct such a model for a system, and since the resulting state-level model can involve a huge number of states, model analysis can be difficult or impossible. Here, we describe methods for the high-level specification of a system using hypergraphs, for the automated generation of a state-level model from a high-level model, and for the exact reduction of a state-level model using information from the high-level model. Exact reduction is achieved through the automated application of symmetry reduction and invariant manifold reduction techniques to the high-level model, allowing potentially significant reductions without the need to generate a full model. The application of the method to biochemical reaction systems is illustrated by models describing a hypothetical ion-channel at several levels of complexity. The method allows for the reduction of the otherwise intractable example models to a manageable size.

physics.chem-ph↗

arXiv2010

Analysis of Diffusion of Ras2 in Saccharomyces cerevisiae Using Fluorescence Recovery after Photobleaching

Binding, lateral diffusion and exchange are fundamental dynamic processes involved in protein association with cellular membranes. In this study, we developed numerical simulations of lateral diffusion and exchange of fluorophores in membranes with arbitrary bleach geometry and exchange of the membrane localized fluorophore with the cytosol during Fluorescence Recovery after Photobleaching (FRAP) experiments. The model simulations were used to design FRAP experiments with varying bleach region sizes on plasma-membrane localized wild type GFP-Ras2 with a dual lipid anchor and mutant GFP-Ras2C318S with a single lipid anchor in live yeast cells to investigate diffusional mobility and the presence of any exchange processes operating in the time scale of our experiments. Model parameters estimated using data from FRAP experiments with a 1 micron x 1 micron bleach region-of-interest (ROI) and a 0.5 micron x 0.5 micron bleach ROI showed that GFP-Ras2, single or dual lipid modified, diffuses as single species with no evidence of exchange with a cytoplasmic pool. This is the first report of Ras2 mobility in yeast plasma membrane. The methods developed in this study are generally applicable for studying diffusion and exchange of membrane associated fluorophores using FRAP on commercial confocal laser scanning microscopes.

q-bio.SC↗

arXiv2010

An annotated English translation of `Kinetics of stationary reactions' [M. I. Temkin, Dolk. Akad. Nauk SSSR. 152, 156 (1963)]

Temkin's 1963 article on one-way fluxes and flux ratios in steady-state reaction systems bears directly on current research in physical and biological chemistry, such as in the interpretation of metabolic exchange fluxes determined from isotopomer labeling experiments. Yet, originally published in Russian [Dolk. Akad. Nauk SSSR 152, 156-159 (1963)], this article has remained inaccessible to much of the scientific community. Here we provide an English translation of the original article with several additional clarifications and corrections.

physics.chem-ph↗

arXiv2007

Directionality is an inherent property of biochemical networks

Thermodynamic constraints on reactions directions are inherent in the structure of a given biochemical network. However, concrete procedures for determining feasible reaction directions for large-scale metabolic networks are not well established. This work introduces a systematic approach to compute reaction directions, which are constrained by mass balance and thermodynamics, for genome-scale networks. In addition, it is shown that the nonconvex solution space constrained by physicochemical constraints can be approximated by a set of linearized subspaces in which mass and thermodynamic balance are guaranteed. The developed methodology can be used to {\it ab initio} predict reaction directions of genome-scale networks based solely on the network stoichoimetry.

q-bio.MN↗

arXiv2006

Relationship between Thermodynamic Driving Force and One-Way Fluxes in Reversible Chemical Reactions

Chemical reaction systems operating in nonequilibrium open-system states arise in a great number of contexts, including the study of living organisms, in which chemical reactions, in general, are far from equilibrium. Here we introduce a theorem that relates forward and re-verse fluxes and free energy for any chemical process operating in a steady state. This rela-tionship, which is a generalization of equilibrium conditions to the case of a chemical process occurring in a nonequilibrium steady state, provides a novel equivalent definition for chemical reaction free energy. In addition, it is shown that previously unrelated theories introduced by Ussing and Hodgkin and Huxley for transport of ions across membranes, Hill for catalytic cycle fluxes, and Crooks for entropy production in microscopically reversible systems, are united in a common framework based on this relationship.

q-bio.SC↗

arXiv2006

Metabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control

It has long been hypothesized that futile cycles in cellular metabolism are involved in the regulation of biochemical pathways. Following the work of Newsholme and Crabtree, we develop a quantitative theory for this idea based on open-system thermodynamics and metabolic control analysis. It is shown that the {\it stoichiometric sensitivity} of an intermediary metabolite concentration with respect to changes in steady-state flux is governed by the effective equilibrium constant of the intermediate formation, and the equilibrium can be regulated by a futile cycle. The direction of the shift in the effective equilibrium constant depends on the direction of operation of the futile cycle. High stoichiometric sensitivity corresponds to ultrasensitivity of an intermediate concentration to net flow through a pathway; low stoichiometric sensitivity corresponds to super-robustness of concentration with respect to changes in flux. Both cases potentially play important roles in metabolic regulation. Futile cycles actively shift the effective equilibrium by expending energy; the magnitude of changes in effective equilibria and sensitivities is a function of the amount of energy used by a futile cycle. This proposed mechanism for control by futile cycles works remarkably similarly to kinetic proofreading in biosynthesis. The sensitivity of the system is also intimately related to the rate of concentration fluctuations of intermediate metabolites. The possibly different roles of the two major mechanisms for cellular biochemical regulation, namely reversible chemical modifications via futile cycles and shifting equilibrium by macromolecular binding, are discussed.

q-bio.SC↗