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Lloyd Demetrius

Publications and source records attributed to Lloyd Demetrius.

13 recordsLinked to original sources
PubMed2006

An entropic characterization of protein interaction networks and cellular robustness.

The structure of molecular networks is believed to determine important aspects of their cellular function, such as the organismal resilience against random perturbations. Ultimately, however, cellular behaviour is determined by the dynamical processes, which are constrained by network topology. The present work is based on a fundamental relation from dynamical systems theory, which states that the macroscopic resilience of a steady state is correlated with the uncertainty in the underlying microscopic processes, a property that can be measured by entropy. Here, we use recent network data from large-scale protein interaction screens to characterize the diversity of possible pathways in terms of network entropy. This measure has its origin in statistical mechanics and amounts to a global characterization of both structural and dynamical resilience in terms of microscopic elements. We demonstrate how this approach can be used to rank network elements according to their contribution to network entropy and also investigate how this suggested ranking reflects on the functional data provided by gene knockouts and RNAi experiments in yeast and Caenorhabditis elegans. Our analysis shows that knockouts of proteins with large contribution to network entropy are preferentially lethal. This observation is robust with respect to several possible errors and biases in the experimental data. It underscores the significance of entropy as a fundamental invariant of the dynamical system, and as a measure of structural and dynamical properties of networks. Our analytical approach goes beyond the phenomenological studies of cellular robustness based on local network observables, such as connectivity. One of its principal achievements is to provide a rationale to study proxies of cellular resilience and rank proteins according to their importance within the global network context.

Computer Simulation↗
PubMed2006

The origin of allometric scaling laws in biology.

The empirical rules relating metabolic rate and body size are described in terms of (i) a scaling exponent, which refers to the ratio of the fractional change in metabolic rate to a change in body size, (ii) a proportionality constant, which describes the rate of energy expenditure in an organism of unit mass. This article integrates the chemiosmotic theory of energy transduction with the methods of quantum statistics to propose a molecular mechanism which, in sharp contrast to competing models, explains both the variation in scaling exponents and the taxon-specific differences in proportionality constants. The new model is universal in the sense that it applies to unicellular organisms, plants and animals.

Animals↗
PubMed2006

The dietary restriction effect in C. elegans and humans: is the worm a one-millimeter human?

Dietary restriction (DR) lengthens life span in wide range of vertebrate and invertebrate species. The molecular mechanism by which DR increases life span and the universality of its effects (and hence its applicability to humans) are currently debated in gerontology. This article addresses these two problems from both an experimental perspective, using the nematode C. elegans as a model system, and a theoretical viewpoint, by appealing to recent mechanistic and evolutionary models of aging. Molecular mechanisms of aging are analysed by contrasting the rate of living/oxidative stress hypothesis with the metabolic stability/longevity hypothesis, a new model of aging which postulates that the robustness of metabolic networks, rather than metabolic rate per se, is the major determinant of aging. Studies of food-restricted worms are shown to be consistent with the metabolic stability/longevity hypothesis. The universality of the effects of DR is addressed in terms of directionality theory, an evolutionary model, which is based on the analytical fact that the robustness or the stability of demographic networks determines Darwinian fitness. Directionality theory, in conjunction with the metabolic stability hypothesis, predicts that DR will have negligible effects on equilibrium species (late age of sexual maturity, small size of progeny sets and broad reproductive span) and large effects on opportunistic species (early age of maturity, large size of progeny sets, narrow reproductive span). Empirical studies using C. elegans (an opportunistic species) and computational studies on human populations (an equilibrium species) are shown to be consistent with these predictions.

Aging↗
PubMed2006

Aging in mouse and human systems: a comparative study.

This article discusses the significance of mouse models as a basis for elucidating the aging process in humans. We identify certain parallels between mouse and human systems and review the theoretical and empirical support for the claim that the large divergence in the rate of aging between the two species resides in differences in the stability of their metabolic networks. We will show that these differences in metabolic stability have their origin in the different ecological constraints the species experience during their evolutionary history. We exploit these ideas to compare the effect of caloric restriction on murine and human systems. The studies predict that the large increases in mean life span and maximum life-span potential observed in laboratory rodents subject to caloric restriction will not obtain in human populations. We predict that, in view of the different metabolic stability of the two systems, caloric restriction will have no effect on the maximum life-span potential of humans, and a relatively minor effect on the mean life span of nonobese populations. This article thus points to certain intrinsic limitations in the use of mouse models in elucidating the aging process in humans. We furthermore contend the view that these limitations can be mitigated by considering the metabolic stability of the two species.

Aging↗
PubMed2005

Stability constraints and protein evolution: the role of chain length, composition and disulfide bonds.

Stability of the native state is an essential requirement in protein evolution and design. Here we investigated the interplay between chain length and stability constraints using a simple model of protein folding and a statistical study of the Protein Data Bank. We distinguish two types of stability of the native state: with respect to the unfolded state (unfolding stability) and with respect to misfolded configurations (misfolding stability). Several contributions to stability are evaluated and their correlations are disentangled through principal components analysis, with the following main results. (1) We show that longer proteins can fulfil more easily the requirements of unfolding and misfolding stability, because they have a higher number of native interactions per residue. Consistently, in longer proteins native interactions are weaker and they are less optimized with respect to non-native interactions. (2) Stability against misfolding is negatively correlated with the strength of native interactions, which is related to hydrophobicity. Hence there is a trade-off between unfolding and misfolding stability. This trade-off is influenced by protein length: less hydrophobic sequences are observed in very long proteins. (3) The number of disulfide bonds is positively correlated with the deficit of free energy stabilizing the native state. Chain length and the number of disulfide bonds per residue are negatively correlated in proteins with short chains and uncorrelated in proteins with long chains. (4) The number of salt bridges per residue and per native contact increases with chain length. We interpret these observations as an indication that the constraints imposed by unfolding stability are less demanding in long proteins and they are further reduced by the competing requirement for stability against misfolding. In particular, disulfide bonds appear to be positively selected in short proteins, whereas they evolve in an effectively neutral way in long proteins.

Amino Acids↗
PubMed2005

Directionality theory: an empirical study of an entropic principle in life-history evolution.

Understanding the relationship between ecological constraints and life-history properties constitutes a central problem in evolutionary ecology. Directionality theory, a model of the evolutionary process based on demographic entropy, a measure of the uncertainty in the age of the mother of a randomly chosen newborn, provides an analytical framework for addressing this problem. The theory predicts that in populations that spend the greater part of their evolutionary history in the stationary growth phase (equilibrium species), entropy will increase. Equilibrium species will be characterized by high iteroparity and strong demographic stability. In populations that spend the greater part of their evolutionary history in the exponential growth phase (opportunistic species), entropy will decrease when population size is large, and will undergo random variation when population size is small. Opportunistic species will be characterized by weak iteroparity and weak demographic stability when population size is large, and random variations in these attributes when population size is small. This paper assesses the validity of these predictions by employing a demographic dataset of 66 species of perennial plants. This empirical analysis is consistent with directionality theory and provides support for its significance as an explanatory and predictive model of life-history evolution.

Age Factors↗
PubMed2005

Directionality theory: a computational study of an entropic principle in evolutionary processes.

Analytical studies of evolutionary processes based on the demographic parameter entropy-a measure of the uncertainty in the age of the mother of a randomly chosen newborn-show that evolutionary changes in entropy are contingent on environmental constraints and can be characterized in terms of three tenets: (i) a unidirectional increase in entropy for populations subject to bounded growth constraints; (ii) a unidirectional decrease in entropy for large populations subject to unbounded growth constraints; (iii) random, non-directional change in entropy for small populations subject to unbounded growth constraints. This article aims to assess the robustness of these analytical tenets by computer simulation. The results of the computational study are shown to be consistent with the analytical predictions. Computational analysis, together with complementary empirical studies of evolutionary changes in entropy underscore the universality of the entropic principle as a model of the evolutionary process.

Biological Evolution↗
PubMed2005

Lethality and entropy of protein interaction networks.

We characterize protein interaction networks in terms of network entropy. This approach suggests a ranking principle, which strongly correlates with elements of functional importance, such as lethal proteins. Our combined analysis of protein interaction networks and functional profiles in single cellular yeast and multi-cellular worm shows that proteins with large contribution to network entropy are preferentially lethal. While entropy is inherently a dynamical concept, the present analysis incorporates only structural information. Our result therefore highlights the importance of topological features, which appear as correlates of an underlying dynamical property, and which in turn determine functional traits. We argue that network entropy is a natural extension of previously studied observables, such as pathway multiplicity and centrality. It is also applicable to networks in which the processes can be quantified and therefore serves as a link to study questions of structural and dynamical robustness in a unified way.

Animals↗
PubMed2004

Complexity and demographic stability in population models.

This article is concerned with relating the stability of a population, as defined by the rate of decay of fluctuations induced by demographic stochasticity, with its heterogeneity in age-specific birth and death rates. We invoke the theory of large deviations to establish a fluctuation theorem: The demographic stability of a population is positively correlated with evolutionary entropy, a measure of the variability in the age of reproducing individuals in the population. This theorem is exploited to predict certain correlations between ecological constraints and evolutionary trends in demographic stability, namely, (i) bounded growth constraints--a uni-directional increase in stability, (ii) unbounded growth constraints (large population size)--a uni-directional decrease in stability, (iii) unbounded growth constraints (small population size)--random, non-directional change in stability. These principles relating ecological constraints with trends in demographic stability are shown to be far reaching generalizations of the tenets derived from classical studies of stability in an evolutionary context. These results thus provide a new conceptual framework for explaining patterns of variation in population numbers observed in natural populations.

Age Factors↗
PubMed2004

Caloric restriction, metabolic rate, and entropy.

Caloric restriction increases life span in many types of animals. This article proposes a mechanism for this effect based on the hypothesis that metabolic stability, the capacity of an organism to maintain steady state values of redox couples, is a prime determinant of longevity. We integrate the stability-longevity hypothesis with a molecular model of metabolic activity (quantum metabolism), and an entropic theory of evolutionary change (directionality theory), to propose a proximate mechanism and an evolutionary rationale for aging. The mechanistic features of the new theory of aging are invoked to predict that caloric restriction extends life span by increasing metabolic stability. The evolutionary model is exploited to predict that the large increases in life span under caloric restriction observed in rats, a species with early sexual maturity, narrow reproductive span and large litter size, and hence low entropy, will not hold for primates. We affirm that in the case of humans, a species with late sexual maturity, broad reproductive span and small litter size, and hence high entropy, the response of life span to caloric restriction will be negligible.

Animals↗
PubMed2002

Thermodynamics and kinetics of protein folding: an evolutionary perspective.

This article appeals to an evolutionary model which postulates that primordial proteins were described by small polypeptide chains which (i) lack disulfide bridges, and (ii) display slow folding rates with multi-state kinetics, to determine relations between structural properties of proteins and their folding kinetics. We parameterize the energy landscape of proteins in terms of thermodynamic activation variables. The model studies evolutionary changes in these thermodynamic parameters, and we invoke relations between these activation variables and structural properties of the protein to predict the following correspondence between protein structure and folding kinetics. 1. Proteins with inter- and intra-chain disulfide bridges: large variability in both folding rates and stability of intermediates, multi-state kinetics. 2. Proteins which lack inter and intra-chain disulfide bridges. 2.1 Single-domain chains: fast folding rates; unstable intermediates; two-state kinetics. 2.2 Multi-domain monomers: intermediate rates; metastable intermediates; multi-state kinetics. 2.3 Multi-domain oligomers: slow rates; metastable intermediates; multi-state kinetics. The evolutionary model thus provides a kinetic characterization of one important subfamily of proteins which we describe by the following properties: Folding dynamics of single-domain proteins which lack disulfide bridges are described by two-state kinetics. Folding rate of this class of proteins is positively correlated with the thermodynamic stability of the folded state.

Disulfides↗