Site-Specific thermodynamics of ising networks: A theorem for linearly connected subsystems

An Ising network consists of a set of N units existing in two possible states, 0 and 1. If two units contact each other in the network, there is a nearest neighbor interaction that depends only on the states of the units. If an Ising network can be split into two independent subsystems by deleting the contact between two units, then these units specify each other's site-specific properties and the state of either unit uniquely specifies the state of the other. This theorem holds regardless of (a) the dimensional embedding of the network as a whole, (b) the precise interaction geometry among the units within either subsystem, and (c) the intrinsic energy for the 0 → 1 switching of any given unit. Either subsystem in the network can be considered as a probe for the state of the unit in the other subsystem to which the probe is connected. Application of the theorem to the analysis of the site-specific properties of the biologically relevant case of a linear network, or heteropolymer, yields a rather counterintuitive result. Knowledge of the state of the end unit in the network, as a function of the change in the thermodynamic driving force for the 0 → 1 transition, is sufficient to completely resolve the energetics of the network. © 1994 John Wiley & Sons, Inc.     

Effects of monofunctional adducts of platinum(II) complexes on thermodynamic stability and energetics of DNA duplexes

Effects of adducts of [PtCl(NH3)3]Cl or chlorodiethylenetriamineplatinum(II) on DNA stability were studied with emphasis on thermodynamic origins of that stability. Oligodeoxyribonucleotide duplexes (15-bp) containing the single, site-specific monofunctional adduct at G-residues of the central sequences TGT/ACA or 5'-AGT/5'-ACT were prepared and analyzed by differential scanning calorimetry, temperature-dependent ultraviolet absorption and circular dichroism. The unfolding of the platinated duplexes was accompanied by relatively small unfavorable free energy terms. This destabilization was enthalpic in origin. On the other hand, a relatively large reduction of melting temperature (T(m)) was observed as a consequence of the monofunctional adduct in the TGT sequence, whereas T(m) due to the adduct in the AGT sequence was reduced only slightly. We also examined the efficiency of the mammalian nucleotide excision repair system to remove from DNA the monofunctional adducts and found that these lesions were not recognized by this repair system. Thus, rather thermodynamic than thermal characterization of DNA adducts of monofunctional platinum compounds is a property implicated in the modulation of downstream effects such as protein recognition and repair.     

Graphic modeling of epithelial transport system: causality of dissipation

The epithelial transport system is a thermodynamic system which is composed of membranes and fluid compartments. The membranes are assumed to be dissipative subsystems in which power dissipates, and fluid compartments are capacitive subsystems in which power is stored. Each subsystem can be subdivided into elementary thermodynamic processes, and can be represented by generalized capacitors, power transducers and resistors in a bond graph. In the modeling of the dissipative subsystem, the causality of the dissipative process was taken into consideration and the representation of power coupling was developed. The dissipative subsystem can be represented by a combination of coupling modules and conductors. Phenomenological equations with parameters from the model were derived. This study shows that the behavior of transport systems can be simulated using these equations.     

The geometry of multisite phosphorylation

Reversible protein phosphorylation on multiple sites is a key regulatory mechanism in most cellular processes. We consider here a kinase-phosphatase-substrate system with two sites, under mass-action kinetics, with no restrictions on the order of phosphorylation or dephosphorylation. We show that the concentrations of the four phosphoforms at steady state satisfy an algebraic formula—an invariant—that is independent of the other chemical species, such as free enzymes or enzyme-substrate complexes, and holds irrespective of the starting conditions and the total amounts of enzymes and substrate. Such invariants allow stringent quantitative predictions to be made without requiring any knowledge of site-specific parameter values. We introduce what we believe are novel methods from algebraic geometry—Gröbner bases, rational curves—to calculate invariants. These methods are particularly significant because they make it possible to treat parameters symbolically without having to specify their numerical values, and thereby allow us to sidestep the parameter problem. We anticipate that this approach will have much wider applications in biological modeling.     

Presence of Nonlinear Excitations in DNA Structure and their Relationship to DNA Premelting and to Drug Intercalation

Abstract

We propose that collectively localized nonlinear excitations (solitons) exist in DNA structure. These arise as a consequence of an intrinsic nonlinear ribose inversion instability that results in a modulated β alternation in sugar puckering along the polymer backbone. In their bound state, soliton-antisoliton pairs contain β premelted core regions capable of undergoing breathing motions that facilitate drug intercalation. We call such bound state structures—β premeltons. The stability of a β premelton is expected to reflect the collective properties of extended DNA regions and to be sensitive to temperature, pH, ionic strength and other thermodynamic factors. Its tendency to localize at specific nucleotide base sequences may serve to initiate site-specific DNA premelting and melting. We suggest that β premeltons provide nucleation centers important for RNA polymerase-promoter recognition. Such nucleation centers could also correspond to nuclease hypersensitive sites.     

Prospects for Studies of Morphological Variability of Land Pulmonate Snails

The main goal of modern investigations into the morphological variability of land pulmonate snails was defined as designing the patterns of taxa structure on the basis of historical analysis of their taxonomic studies. Transition from the investigation of individual characters to an analysis of the organism as a whole assumes the application of the system approach. Systemic properties of the organism can be revealed through the key characters reflecting the process of evolutionary transformation of the correlation chains. In the case of land pulmonate snails, the relationship between the operative and conservative subsystems of the organism can serve as such a key character. The operative subsystem-cephalopodium-fulfills the function of active contacts with the environment; the conservative subsystem-the shell and its content-exercises protective functions. The subsystems are in conflict, and its resolution establishes the main patterns of the organization of pulmonate snails.     

Greek derivational structures: restrictions and constraints

This paper investigates the general principles governing the combination of a base with a particular suffix. Elaborating on the well-known conflict between base-driven and affix-driven selectional restrictions, we argue in favor of affix-driven selection. We claim that the various selectional restrictions imposed by the suffixes are inherent specifications, which characterize their entries at the lexical level; if suffixes are heads of derivational structures, these restrictions pass from heads to the derived items through percolation. Additionally, we propose that, beside selectional restrictions, the combinatorial behaviour of suffixes may be determined by a number of other lexically-specified properties such as the ‘unique suffix’ or ‘closing suffix’. Finally, we claim that derivational structures are also governed by language-independent or language-specific constraints, operating on input structures.     

Structural and thermodynamic strategies for site-specific DNA binding proteins

BACKGROUND: Site-specific protein-DNA complexes vary greatly in structural properties and in the thermodynamic strategy for achieving an appropriate binding free energy. A better understanding of the structural and energetic engineering principles might lead to rational methods for modification or design of such proteins. RESULTS: A novel analysis of ten site-specific protein-DNA complexes reveals a striking correspondence between the degree of imposed DNA distortion and the thermodynamic parameters of each system. For complexes with relatively undistorted DNA, favorable enthalpy change drives unfavorable entropy change, whereas for complexes with highly distorted DNA, unfavorable DeltaH degrees is driven by favorable DeltaS degrees. We show for the first time that protein-DNA associations have isothermal enthalpy-entropy compensation, distinct from temperature-dependent compensation, so DeltaH degrees and DeltaS degrees do not vary independently. All complexes have favorable DeltaH degrees from direct protein-DNA recognition interactions and favorable DeltaS degrees from water release. Systems that strongly distort the DNA nevertheless have net unfavorable DeltaH degrees as the result of molecular strain, primarily associated with the base pair destacking. These systems have little coupled protein folding and the strained interface suffers less immobilization, so DeltaS degrees is net favorable. By contrast, systems with little DNA distortion have net favorable DeltaH degrees, which must be counterbalanced by net unfavorable DeltaS degrees, derived from loss of vibrational entropy (a result of isothermal enthalpy-entropy compensation) and from coupling between DNA binding and protein folding. CONCLUSIONS: Isothermal enthalpy-entropy compensation implies that a structurally optimal, unstrained fit is achieved only at the cost of entropically unfavorable immobilization, whereas an enthalpically weaker, strained interface entails smaller entropic penalties.     

Atomic resolution structures of rieske iron-sulfur protein: role of hydrogen bonds in tuning the redox potential of iron-sulfur clusters

The Rieske [2Fe-2S] iron-sulfur protein of cytochrome bc(1) functions as the initial electron acceptor in the rate-limiting step of the catalytic reaction. Prior studies have established roles for a number of conserved residues that hydrogen bond to ligands of the [2Fe-2S] cluster. We have constructed site-specific variants at two of these residues, measured their thermodynamic and functional properties, and determined atomic resolution X-ray crystal structures for the native protein at 1.2 A resolution and for five variants (Ser-154-->Ala, Ser-154-->Thr, Ser-154-->Cys, Tyr-156-->Phe, and Tyr-156-->Trp) to resolutions between 1.5 A and 1.1 A. These structures and complementary biophysical data provide a molecular framework for understanding the role hydrogen bonds to the cluster play in tuning thermodynamic properties, and hence the rate of this bioenergetic reaction. These studies provide a detailed structure-function dissection of the role of hydrogen bonds in tuning the redox potentials of [2Fe-2S] clusters.     

Looking at structure, stability, and evolution of proteins through the principal eigenvector of contact matrices and hydrophobicity profiles

We review and further develop an analytical model that describes how thermodynamic constraints on the stability of the native state influence protein evolution in a site-specific manner. To this end, we represent both protein sequences and protein structures as vectors: structures are represented by the principal eigenvector (PE) of the protein contact matrix, a quantity that resembles closely the effective connectivity of each site; sequences are represented through the "interactivity" of each amino acid type, using novel parameters that are correlated with hydropathy scales. These interactivity parameters are more strongly correlated than the other hydropathy scales that we examine with: (1) the change upon mutations of the unfolding free energy of proteins with two-states thermodynamics; (2) genomic properties as the genome-size and the genome-wide GC content; (3) the main eigenvectors of the substitution matrices. The evolutionary average of the interactivity vector correlates very strongly with the PE of a protein structure. Using this result, we derive an analytic expression for site-specific distributions of amino acids across protein families in the form of Boltzmann distributions whose "inverse temperature" is a function of the PE component. We show that our predictions are in agreement with site-specific amino acid distributions obtained from the Protein Data Bank, and we determine the mutational model that best fits the observed site-specific amino acid distributions. Interestingly, the optimal model almost minimizes the rate at which deleterious mutations are eliminated by natural selection.     

Impact of long-term cropping of glyphosate-resistant transgenic soybean [<Emphasis Type="Italic">Glycine max</Emphasis> (L.) Merr.] on soil microbiome

The transgenic soybean [Glycine max (L.) Merrill] occupies about 80 % of the global area cropped with this legume, the majority comprising the glyphosate-resistant trait (Roundup Ready^®, GR or RR). However, concerns about possible impacts of transgenic crops on soil microbial communities are often raised. We investigated soil chemical, physical and microbiological properties, and grain yields in long-term field trials involving conventional and nearly isogenic RR transgenic genotypes. The trials were performed at two locations in Brazil, with different edaphoclimatic conditions. Large differences in physical, chemical and classic microbiological parameters (microbial biomass of C and N, basal respiration), as well as in grain production were observed between the sites. Some phyla (Proteobacteria, Actinobacteria, Acidobacteria), classes (Alphaproteobacteria, Actinomycetales, Solibacteres) and orders (Rhizobiales, Burkholderiales, Myxococcales, Pseudomonadales), as well as some functional subsystems (clustering-based subsystems, carbohydrates, amino acids and protein metabolism) were, in general, abundant in all treatments. However, bioindicators related to superior soil fertility and physical properties at Londrina were identified, among them a higher ratio of Proteobacteria:Acidobacteria. Regarding the transgene, the metagenomics showed differences in microbial taxonomic and functional abundances, but lower in magnitude than differences observed between the sites. Besides the site-specific differences, Proteobacteria, Firmicutes and Chlorophyta were higher in the transgenic treatment, as well as sequences related to protein metabolism, cell division and cycle. Although confirming effects of the transgenic trait on soil microbiome, no differences were recorded in grain yields, probably due to the buffering capacity associated with the high taxonomic and functional microbial diversity observed in all treatments.     

An ultrasensitive site-specific DNA recombination assay based on dual-color fluorescence cross-correlation spectroscopy

Site-specific exchange of genetic information is mediated by DNA recombinases, such as FLP or Cre, and has become a valuable tool in modern molecular biology. The so far low number of suitable recombinating enzymes has driven current research activities towards alteration of catalytic properties, such as thermostability or recognition sequences. However, identification and analysis of new mutants requires sensitive in vitro activity assays, which traditionally are based on gel electrophoresis. Here, we describe the development of a new sensitive DNA recombination assay based on dual-color fluorescence cross-correlation spectroscopy (DC-FCCS), which works in homogenous solution and does not require any separation step such as electrophoresis. The assay was validated with unlabeled FLP recombinase and different fluorescently labeled DNA substrates containing the FLP recognition target (FRT). This strategy fulfills all requirements for possible application in high throughput screening and engineering of new site-specific DNA recombinases starting from the FLP-FRT system, and is easily adjustable to other systems like Cre/loxP.     

Presence of nonlinear excitations in DNA structure and their relationship to DNA premelting and to drug intercalation

We propose that collectively localized nonlinear excitations (solitons) exist in DNA structure. These arise as a consequence of an intrinsic nonlinear ribose inversion instability that results in a modulated beta alternation in sugar puckering along the polymer backbone. In their bound state, soliton-antisoliton pairs contain beta premelted core regions capable of undergoing breathing motions that facilitate drug intercalation. We call such bound state structures--beta premeltons. The stability of a beta premelton is expected to reflect the collective properties of extended DNA regions and to be sensitive to temperature, pH, ionic strength and other thermodynamic factors. Its tendency to localize at specific nucleotide base sequences may serve to initiate site-specific DNA premelting and melting. We suggest that beta premeltons provide nucleation centers important for RNA polymerase-promoter recognition. Such nucleation centers could also correspond to nuclease hypersensitive sites.     

Qualitative theory of compartmental systems with lags

Dynamic models of many processes in the biological and physical sciences give systems of ordinary differential equations called compartmental systems. Often, these systems include time lags; in this context, continuous probability density functions (pdfs) of lags are far more important than discrete lags. There is a relatively complete theory of compartmental systems without lags, both linear and non-linear [SIAM Rev. 35 (1993) 43]. The authors extend their previous work on compartmental systems without lags to show that, for discrete lags and for a very large class of pdfs of continuous lags, compartmental systems with lags are equivalent to larger compartmental systems without lags. Consequently, the properties of compartmental systems with lags are the same as those of compartmental systems without lags. For a very large class of compartmental systems with time lags, one can show that the time lags themselves can be generated by compartmental systems without lags. Thus, such systems can be partitioned into a main system, which is the original system without the lags, plus compartmental subsystems without lags that generate the lags. The latter may be linear or non-linear and may be inserted into main systems that are linear or non-linear. The state variables of the compartmental lag subsystems are hidden variables in the formulation with explicit lags.     

APPLICATION OF THE DIFFUSION HYPOTHESIS TO MEMBRANE POTENTIALS

A system consisting of two aqueous solutions, containing equal concentrations of lactic acid, but different concentrations of Na lactate, separated by a layer of amyl alcohol has been described. This system exhibits electrical properties ranging (as the concentration of NaL is increased) from those characteristic of a simple Donnan equilibrium to those characteristic of simple diffusion. The fact that the Donnan P.D. can be treated as a special case of a diffusion potential has been emphasized. The experiments call attention to the effect of the thermodynamic properties of the membrane, and it is suggested that such properties as conductivities, ionic mobilities, and distribution coefficients in membranes of any sort should be investigated. The experiments afford an interesting example of "phase reversal."     

On computer simulation methods used to study models of two-component lipid bilayers

We show that the use of a computer simulation method introduced to calculate the equilibrium thermodynamic properties of a model of a two-component lipid bilayer membrane [Freire, E., & Snyder, B. (1980) Biochemistry 19, 88-94] is incorrect. This is done by comparing the method to that of Metropolis, which has been proven to generate equilibrium distribution of that model, and by showing that back-processes have been omitted in the implicit master equation of Freire and Snyder. We have illustrated this explicitly by first generating distributions according to the method of Freire and Snyder and then allowing the system to relax via the Kawasaki method, which uses the technique of Metropolis. We show that relaxation to a different distribution occurs. We also remark that the cluster distributions generated by the Freire-Snyder method are substantially different from those occurring in equilibrium distributions. Thus, conclusions about equilibrium thermodynamic properties such as specific heats and transition enthalpies or about transport properties or cluster properties at equilibrium cannot be drawn from the results obtained by using this method. Finally, we point out that the method of Freire and Snyder is appropriate to so-called aggregation models, which have been used to study irreversible growth; and we suggest biological systems that might be simulated by their method.     

Contractility and conformation

Contractility in fibers can arise from changes of macromolecular conformation caused by changes in some thermodynamic variable such as temperature, pH, or solvent composition. Illustrations are given of contractile processes in fibers and of changes in macromolecular conformation in dilute solution. These may involve order-disorder transitions, e.g. of the type exhibited by the helix-coil transition. A statistical mechanical treatment of the helix-coil transition involves the assignment of statistical weights to various states and the proper counting of these statistical weights in the formation and evaluation of the partition function; the thermodynamic properties of the system are derivable from the partition function. The counting procedure involved in the consideration of the α-helix and random coil is described. In addition, the factors affecting the relative stabilities of various helical conformations are discussed. These considerations of macromolecular conformation provide a basis for discussing contractile mechanisms in which changes of conformation are involved.     

Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease

This study focused on developing a gastroretentive drug delivery system employing a triple-mechanism interpolyelectrolyte complex (IPEC) matrix comprising high density, swelling, and bioadhesiveness for the enhanced site-specific zero-order delivery of levodopa in Parkinson’s disease. An IPEC was synthesized and directly compressed into a levodopa-loaded matrix employing pharmaceutical technology and evaluated with respect to its physicochemical and physicomechanical properties and in vitro drug release. The IPEC-based matrix displayed superior mechanical properties in terms of matrix hardness (34–39 N/mm) and matrix resilience (44–47%) when different normality’s of solvent and blending ratios were employed. Fourier transform infrared spectroscopy confirmed the formation of the IPEC. The formulations exhibited pH and density dependence with desirable gastro-adhesion with Peak Force of Adhesion ranging between 0.15 and 0.21 N/mm, densities from 1.43 to 1.54 g/cm³ and swellability values of 177–234%. The IPEC-based gastroretentive matrix was capable of providing site-specific levodopa release with zero-order kinetics corroborated by detailed mathematical and molecular modeling studies. Overall, results from this study have shown that the IPEC-based matrix has the potential to improve the absorption and subsequent bioavailability of narrow absorption window drugs, such as levodopa with constant and sustained drug delivery.     

APUAMA: a software tool for reaction rate calculations

APUAMA is a free software designed to determine the reaction rate and thermodynamic properties of chemical species of a reagent system. With data from electronic structure calculations, the APUAMA determine the rate constant with tunneling correction, such as Wigner, Eckart and small curvature, and also, include the rovibrational level of diatomic molecules. The results are presented in the form of Arrhenius-Kooij form, for the reaction rate, and the thermodynamic properties are written down in the polynomial form. The word APUAMA means “fast” in Tupi-Guarani Brazilian language, then the code calculates the reaction rate on a simple and intuitive graphic interface, the form fast and practical. As program output, there are several ASCII files with tabulated information for rate constant, rovibrational levels, energy barriers and enthalpy of reaction, Arrhenius-Kooij coefficient, and also, the option to the User save all graphics in BMP format.