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At least 19 recordsLinked to original sources

arXiv2006

Traffic of interacting ribosomes: effects of single-machine mechano-chemistry on protein synthesis

Many ribosomes simultaneously move on the same messenger RNA (mRNA), each separately synthesizing the protein coded by the mRNA. Earlier models of ribosome traffic represent each ribosome by a ``self-propelled particle'' and capture the dynamics by an extension of the totally asymmetric simple exclusion process (TASEP). In contrast, here we develope a theoretical model that not only incorporates the mutual exclusions of the interacting ribosomes, but also describes explicitly the mechano-chemistry of each of these individual cyclic machines during protein synthesis. Using analytical and numerical techniques of non-equilibrium statistical mechanics, we analyze this model and illustrate its power by making experimentally testable predictions on the rate of protein synthesis in real time and the density profile of the ribosomes on some mRNAs in E-Coli.

physics.bio-ph↗

arXiv2011

Stall force of polymerizing microtubules and filament bundles

We investigate stall force and polymerization kinetics of rigid protofilaments in a microtubule or interacting filaments in bundles under an external load force in the framework of a discrete growth model. We introduce the concecpt of polymerization cycles to describe the stochastic growth kinetics, which allows us to derive an exact expression for the stall force. We find that the stall force is independent of ensemble geometry and load distribution. Furthermore, the stall force is proportional to the number of filaments and increases linearly with the strength of lateral filament interactions. These results are corroborated by simulations, which also show a strong influence of ensemble geometry on growth kinetics below the stall force.

cond-mat.stat-mech↗

arXiv2018

The mre11 A470 Alleles Influence the. Heritability and Segregation of Telosomes in Saccharomyces cerevisiae

Telomeres, the nucleoprotein complexes at the termini of linear chromosomes, are essential for the processes of end replication, end-protection, and chromatin segregation. The Mre11 complex is involved in multiple cellular roles in DNA repair and structure in the regulation and function of telomere size homeostasis. In this study, we characterize yeast telomere chromatin structure, phenotypic heritability, and chromatin segregation in both wild-type [MRE11] and A470 motif alleles. MRE11 strains confer a telomere size of 300 base pairs of G+T irregular simple sequence repeats. This DNA and a portion of subtelomeric DNA is embedded in a telosome: an MNase-resistant non-nucleosomal particle. Chromatin immunoprecipitation shows a three to four-fold lower occupancy of Mre11A470T proteins than wild-type proteins in telosomes. Telosomes containing the Mre11A470T protein confer a greater resistance to MNase digestion than wild-type telosomes. The integration of a wild-type MRE11 allele into an ectopic locus in the genome of a mre11A470T mutant and the introduction of a mre11A470T allele at an ectopic site in a wild-type strain lead to unexpectedly differing results. In each case, the replicated sister chromatids inherit telosomes containing only the protein encoded by the genomic mre11 locus, even in the presence of protein encoded by the opposing ectopic allele. We hypothesize that the telosome segregates by a conservative mechanism. These data support a mechanism for the linkage between sister chromatid replication and maintenance of either identical mutant or identical wild-type telosomes after replication of sister chromatids. These data suggest the presence of an active mechanism for chromatin segregation in yeast.

q-bio.SC↗

arXiv2007

Quantitative Resolution to some "Absolute Discrepancies" in Cancer Theories: a View from Phage lambda Genetic Switch

Is it possible to understand cancer? Or more specifically, is it possible to understand cancer from genetic side? There already many answers in literature. The most optimistic one has claimed that it is mission-possible. Duesberg and his colleagues reviewed the impressive amount of research results on cancer accumulated over 100 years. It confirms the a general opinion that considering all available experimental results and clinical observations there is no cancer theory without major difficulties, including the prevailing gene-based cancer theories. They have then listed 9 "absolute discrepancies" for such cancer theory. In this letter the quantitative evidence against one of their major reasons for dismissing mutation cancer theory, by both in vivo experiment and a first principle computation, is explicitly pointed out.

q-bio.SC↗

arXiv2007

A practical guide to stochastic simulations of reaction-diffusion processes

A practical introduction to stochastic modelling of reaction-diffusion processes is presented. No prior knowledge of stochastic simulations is assumed. The methods are explained using illustrative examples. The article starts with the classical Gillespie algorithm for the stochastic modelling of chemical reactions. Then stochastic algorithms for modelling molecular diffusion are given. Finally, basic stochastic reaction-diffusion methods are presented. The connections between stochastic simulations and deterministic models are explained and basic mathematical tools (e.g. chemical master equation) are presented. The article concludes with an overview of more advanced methods and problems.

q-bio.SC↗

arXiv2007

Efficiency and versatility of distal multisite transcription regulation

Transcription regulation typically involves the binding of proteins over long distances on multiple DNA sites that are brought close to each other by the formation of DNA loops. The inherent complexity of the assembly of regulatory complexes on looped DNA challenges the understanding of even the simplest genetic systems, including the prototypical lac operon. Here we implement a scalable quantitative computational approach to analyze systems regulated through multiple DNA sites with looping. Our approach applied to the lac operon accurately predicts the transcription rate over five orders of magnitude for wild type and seven mutants accounting for all the combinations of deletions of the three operators. A quantitative analysis of the model reveals that the presence of three operators provides a mechanism to combine robust repression with sensitive induction, two seemingly mutually exclusive properties that are required for optimal functioning of metabolic switches.

q-bio.SC↗

arXiv2007

Asymptotic velocity of one dimensional diffusions with periodic drift

We consider the asymptotic behaviour of the solution of one dimensional stochastic differential equations and Langevin equations in periodic backgrounds with zero average. We prove that in several such models, there is generically a non vanishing asymptotic velocity, despite of the fact that the average of the background is zero.

math.PR↗

arXiv2007

Modeling the effects of HIV-1 virions and proteins on Fas-induced apoptosis of infected cells

We report a first in modeling and simulation of the effects of the HIV proteins on the (caspase dependent) apoptotic pathway in infected cells. This work is novel and is an extension on the recent reports and clarifications on the FAS apoptotic pathway from the literature. We have gathered most of the reaction rates and initial conditions from the literature, the rest of the constants have been computed by fitting our model to the experimental results reported. Using the model obtained we have then run the simulations for the infected memory T cells, called also latent T cells, which, at the moment, represent the major obstacle to finding a cure for HIV. We can now report that the infected latent T cells have an estimated lifetime of about 42 hours from the moment they are re-activated. As far as we know this is the first result of this type obtained for the infected memory T cells.

q-bio.MN↗

arXiv2007

Superdiffusion in a Model for Diffusion in a Molecularly Crowded Environment

We present a model for diffusion in a molecularly crowded environment. The model consists of random barriers in percolation network. Random walks in the presence of slowly moving barriers show normal diffusion for long times, but anomalous diffusion at intermediate times. The effective exponents for square distance versus time usually are below one at these intermediate times, but can be also larger than one for high barrier concentrations. Thus we observe sub- as well as super-diffusion in a crowded environment.

q-bio.SC↗

arXiv2007

Ion transport through cell membrane channels

We discuss various models of ion transport through cell membrane channels. Recent experimental data shows that sizes of ion channels are compared to those of ions and that only few ions may be simultaneously in any single channel. Theoretical description of ion transport in such channels should therefore take into account interactions between ions and between ions and channel proteins. This is not satisfied by macroscopic continuum models based on Poisson-Nernst-Planck equations. More realistic descriptions of ion transport are offered by microscopic Brownian and molecular dynamics. One should also take into account a dynamical character of the channel structure. This is not yet addressed in the literature

q-bio.SC↗

arXiv2007

Free Energy of Activation for the Comorosan Effect

Initial reaction rate data for lactic dehydrogenase / pyruvate, lactic dehydrogenase / lactate and malic dehydrogenase / malate enzyme reactions were analyzed to obtain activation free energy changes of -329, -195 and -221 cal/mole, respectively, for rate increases associated with time-specific irradiation of the crystalline substrates prior to dissolution and incorporation in the reaction solutions. These energies, presumably, correspond to conformational or vibrational changes in the reactants or the activated complex. For the lactic dehydrogenase / pyruvate reaction, it is estimated that on the order of 10% of the irradiation energy (546 nm, 400 footcandles for 5 seconds) would be required to produce the observed reaction rate increase if a presumed photoproduct is consumed stoichiometrically with the pyruvate substrate. These findings are consistent with the proposition that the observed reaction rate enhancement involves photoproducts derived from oscillatory atmospheric gas reactions at the crystalline enzyme substrate surfaces rather than photo-excitations of the substrate molecules, per se.

q-bio.SC↗

arXiv2007

Crystal Irradiation Stimulation of Enzyme Reactivity: An Explanation

In 1968, Sorin Comorosan first reported a phenomenon wherein irradiation of the substrate of an enzyme reaction, in the crystalline state, for a specific number of seconds could lead to an enhanced aqueous solution reaction rate for the enzyme(up to 30%). Dependence on crystal irradiation time was found to be oscillatory with a fixed period. The basis for this unusual phenomenon has remained a mystery. Previously unreported experimental results are presented which demonstrate, for the LDH / pyruvate reaction, that the identity of the crystalline material irradiated is, largely, inconsequential. It is proposed here that the irradiation procedure drives oscillatory reactions involving atmospheric gases adsorbed on the crystals and that these photoproducts, or related dark-reaction species, when dissolved, function as enzyme cofactors.

q-bio.SC↗

arXiv2007

Antiproliferative MCR peptides block physical interaction of insulin with retinoblastoma protein (RB) in human lung cancer cells

Fifteen years ago, a structural analysis of the hormone insulin and the retinoblastoma tumor suppressor protein (RB) revealed that they may physically interact with one another. Subsequently, an RB peptide corresponding to the proposed RB binding site for insulin was found to recognize full-length insulin in vitro. As part of efforts aimed at developing this RB peptide into an anti-cancer drug, this molecule was chemically coupled to a cellular internalization signal and termed "MCR peptide". Meanwhile, several such MCR peptide variants have been demonstrated to restrain the proliferation of different human cancer cells in vitro and in vivo. Moreover, one of the MCR peptides coined MCR-10 was shown to be capable of interfering with the complex formation between insulin and RB in HepG2 human hepatoma cells, as monitored by immunofluorescence. This latter result indicating an in vivo association between insulin and RB was confirmed by a follow-up study combining the methods of co-immunoprecipitation and immunoblotting. Here, we provide evidence for the existence of the insulin-RB complex in A549 human non-small cell lung cancer cells. Specifically, we demonstrate this heterodimer by means of a magnetic beads-based immunoprecipitation approach and equally show that this dimer can be disrupted by MCR-4 or MCR-10 each of which is known to possess antiproliferative properties, yet to a much lesser extent by a control peptide. Thus, this investigation has yielded another important proof for the occurrence of the insulin-RB dimer and, furthermore, its validity as a target for antineoplastic MCR peptides.

q-bio.SC↗

arXiv2007

Planet RB: a personal contribution to a proteomic map of human retinoblastoma protein

As I compress on the canvas of a few pages here major results of my research on the retinoblastoma tumor suppressor protein (RB) spreading over the past 15 years, an exciting picture emerges on this unique host molecule which surpasses in its complexity even that of the most capable viral proteins known to date. Accordingly, RB has the potential to bind not only growth-promoting proteins such as insulin, but also to attach itself to calcium and oxygen, as well as to be secreted into the extracellular environment. Moreover, RB may exert proteolytic, antimicrobial and anti-aging activities. These condensed structure-based insights on RB are the substance of a scientific revolution I have initiated a long time ago, yet likely to gain even further speed in the years to come, thus expanding both our understanding of life at the molecular level and the possibilities for pharmacological modulation of fundamental biological phenomena, particularly in oncology and gerontology.

q-bio.BM↗

arXiv2007

Stability in generic mitochondrial models

In this paper, we use a variety of mathematical techniques to explore existence, local stability, and global stability of equilibria in abstract models of mitochondrial metabolism. The class of models constructed is defined by the biological description of the system, with minimal mathematical assumptions. The key features are an electron transport chain coupled to a process of charge translocation across a membrane. In the absence of charge translocation these models have previously been shown to behave in a very simple manner with a single, globally stable equilibrium. We show that with charge translocation the conclusion about a unique equilibrium remains true, but local and global stability do not necessarily follow. In sufficiently low dimensions - i.e. for short electron transport chains - it is possible to make claims about local and global stability of the equilibrium. On the other hand, for longer chains, these general claims are no longer valid. Some particular conditions which ensure stability of the equilibrium for chains of arbitrary length are presented.

q-bio.QM↗

arXiv2007

Retinoblastoma protein is the likely common effector for distinct anti-aging pathways

The multiple worlds of genetically manipulated laboratory organisms such as transgenic mice or worms with certain gene mutations are somewhat reminiscent of parallel worlds in quantum mechanics. So are various models of aging tested in such organisms. In this context, the tumor suppressor p53 has been found to either accelerate or delay aging, the latter, for instance, in conjunction with ARF, another tumor suppressor, as shown very recently. To more easily determine which of these artificial settings comes closest to real life, I discuss here their features in the light of my protein structure-based insights that have led me to propose a physiological anti-aging role for the retinoblastoma tumor suppressor protein (RB) over the past four years.

q-bio.SC↗

arXiv2007

The insulin superfamily of growth-promoting proteins

Recently, structural analysis of the human transferrin and growth hormone (GH) amino acid sequences has unravelled that they harbor a motif identical to a pattern found in viral oncoproteins known to bind the primarily nuclear tumor suppressor retinoblastoma protein (RB). Since related signatures had previously been identified also in insulin and the two insulin-like growth factors (IGFs), the aim of the current study has been to investigate whether further hints substantiating these reported homologies can be found in silico. Here, additional similarities are presented supporting the notion of an insulin superfamily of growth-promoting proteins with dual localization in the extracellular environment and the intracellular space, particularly in the nucleus, as well as characterized by a tropism for RB.

q-bio.BM↗

arXiv2007

Distribution of phylogenetic diversity under random extinction

Phylogenetic diversity is a measure for describing how much of an evolutionary tree is spanned by a subset of species. If one applies this to the (unknown) subset of current species that will still be present at some future time, then this `future phylogenetic diversity' provides a measure of the impact of various extinction scenarios in biodiversity conservation. In this paper we study the distribution of future phylogenetic diversity under a simple model of extinction (a generalized `field of bullets' model). We show that the distribution of future phylogenetic diversity converges to a normal distribution as the number of species grows (under mild conditions, which are necessary). We also describe an algorithm to compute the distribution efficiently, provided the edge lengths are integral, and briefly outline the significance of our findings for biodiversity conservation.

q-bio.SC↗