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We discuss two aspects, the in vivo and in vitro difference and the modeling of noise, of integrative modeling of network dynamics in biology, using phage lambda as an example. We believe those two aspects have not been seriously considered, and the including of them may be enough to solve the outstanding stability and robustness puzzle of in gene regulatory network dynamics., Comment: latex, 2 pages

A number of researchers are attempting to develop a biosensor based on terahertz sensing. Key to the realization of any biosensor system is the access of the target molecules to the sensor. In the case of using terahertz spectroscopy, there are limitations due to high attenuation by water and sensitivity levels. In order to have a significant response at THz frequencies generally requires a minimum pathlength of 100 microns. Solid thin films of this thickness will have limited interaction with target molecules. We propose to use xerogels as biomolecular probe substrates. We have characterized the THz transmission of xerogel substrates as a function of hydration and protein content. These measurements demonstrate that xerogels are excellent candidates for biomolecular probe substrates to realize THz biosensors., Comment: single pdf file, 5 pages, 4 figures

We propose a biosensor based on the change of terahertz (THz) dielectric response when a biotarget binds to a probe. The feasibility of this biosensor is examined by studying the change of THz transmission for thin films of heme proteins myoglobin (Mb) and cytochrome C (CytC) as a function oxygen binding. We measure a strong increase in both the index and absorbance with oxygen binding for both Mb and CytC. The measured changes occur for both dried and samples hydrated at 80% r.h. suggesting that using terahertz time domain spectroscopy (TTDS) to monitor the transmitted terahertz pulse through a biomolecular probe thin film in ambient environmental conditions could be used to determine the presence of a biomolecular target., Comment: single pdf file containing figures, 4 pages

We develop a propagating front analysis, in terms of a local probability of zipping, for the helicase activity of opening up a double stranded DNA (dsDNA). In a fixed-distance ensemble (conjugate to the fixed-force ensemble) the front separates the zipped and unzipped phases of a dsDNA and a drive acts locally around the front. Bounds from variational analysis and numerical estimates for the speed of a helicase are obtained. Different types of helicase behaviours can be distinguished by the nature of the drive., Comment: 5 pages, 5 eps figures; replaced by the published version

Adsorption of monovalent and multivalent cat- and anions on a deoxyribose nucleic acid (DNA) molecule from a salt solution is investigated by computer simulation. The ions are modelled as charged hard spheres, the DNA molecule as a point charge pattern following the double-helical phosphate strands. The geometrical shape of the DNA molecules is modelled on different levels ranging from a simple cylindrical shape to structured models which include the major and minor grooves between the phosphate strands. The densities of the ions adsorbed on the phosphate strands, in the major and in the minor grooves are calculated. First, we find that the adsorption pattern on the DNA surface depends strongly on its geometrical shape: counterions adsorb preferentially along the phosphate strands for a cylindrical model shape, but in the minor groove for a geometrically structured model. Second, we find that an addition of monovalent salt ions results in an increase of the charge density in the minor groove while the total charge density of ions adsorbed in the major groove stays unchanged. The adsorbed ion densities are highly structured along the minor groove while they are almost smeared along the major groove. Furthermore, for a fixed amount of added salt, the major groove cationic charge is independent on the counterion valency. For increasing salt concentration the major groove is neutralized while the total charge adsorbed in the minor groove is constant. DNA overcharging is detected for multivalent salt. Simulations for a larger ion radii, which mimic the effect of the ion hydration, indicate an increased adsorbtion of cations in the major groove., Comment: 34 pages with 14 figures

We present a study on filamentous actin solutions containing heavy meromyosin subfragments of myosin II motor molecules. We focus on the viscoelastic phase behavior and internal dynamics of such networks during ATP depletion. Upon simultaneously using micro-rheology and fluorescence microscopy as complementary experimental tools, we find a sol-gel transition accompanied by a sudden onset of directed filament motion. We interpret the sol-gel transition in terms of myosin II enzymology, and suggest a "zipping" mechanism to explain the filament motion in the vicinity of the sol-gel transition., Comment: 4 pages, 3 figures

The respective roles of local and nonlocal interactions in the thermodynamic cooperativity of proteins are investigated using continuum (off-lattice) native-centric G\=o-like models with a coarse-grained C$_\alpha$ chain representation. We study a series of models in which the (local) bond- and torsion-angle terms have different strengths relative to the (nonlocal) pairwise contact energy terms. Conformational distributions in these models are sampled by Langevin dynamics. Thermodynamic cooperativity is characterized by the experimental criteria requiring the van't Hoff to calorimetric enthalpy ratio $\Delta H_{\rm vH}/\Delta H_{\rm cal}\approx 1$ (the calorimetric criterion), as well as a two-state-like variation of the average radius of gyration upon denaturation. We find that both local and nonlocal interactions are critical for thermodynamic cooperativity. Chain models with either much weakened local conformational propensities or much weakened favorable nonlocal interactions are significantly less cooperative than chain models with both strong local propensities and strong favorable nonlocal interactions. These findings are compared with results from a recently proposed lattice model with a local-nonlocal coupling mechanism; their relationship with experimental measurements of protein cooperativity and chain compactness is discussed., Comment: 23 pages, 8 postscript figures (will appear in Polymer)

A theoretical model of a two-component fluid membrane containing lipids and two-state active inclusions is presented. Under strong inclusion activities the membrane can be unstable due to pump-driven undulation or aggregation of high curvature excited inclusions. Depending on the structural details of the inclusions, the active conformation change of the inclusions can also induce finite size domains on the membrane. At long wavelengths a stable membrane has a height fluctuation spectrum similar to previous studies which neglected the inclusion internal states. For a tensionless membrane, $ \sim T_{eff} q_{\perp}^{-4}$, where $T_{eff}$ is an effective temperature which depends on the details of inclusion activities., Comment: 4 pages, 3 figures

Metropolis simulations of all-atom models of peptides (i.e. small proteins) are considered. Inspired by the funnel picture of Bryngelson and Wolyness, a transformation of the updating probabilities of the dihedral angles is defined, which uses probability densities from a higher temperature to improve the algorithmic performance at a lower temperature. The method is suitable for canonical as well as for generalized ensemble simulations. A simple approximation to the full transformation is tested at room temperature for Met-Enkephalin in vacuum. Integrated autocorrelation times are found to be reduced by factors close to two and a similar improvement due to generalized ensemble methods enters multiplicatively., Comment: Plenary talk at the Los Alamos conference, The Monte Carlo Method in Physical Sciences: Celebrating the 50th Anniversary of the Metropolis Algorithm, to appear in the proceedings, 11 pages, 4 figures, one table. Inconsistencies corrected and references added

The morphology and time-evolution of tumors are expected to depend heavily on the detailed balance of the overall physics of the cell assembly (e.g., the kinetic pressure, the cell-cell interaction, and the external trapping by the tissue) and the biological processes of mitosis, necrosis, etc. Here, for the first time, we include such a detailed balance in a theoretical model by exploiting the {\it ab initio} mathematical framework of atomic Bose-Einstein Condensation (BEC) with feeding and dissipation, to study tumor evolution dynamics. We show that, with a characteristic length scaling, the Gross-Pitaevskii (GP) equation, which describes the many-body atomic BEC characteristics, indeed explains the detailed features of a prevascular tumor culture data. The agreement suggests the prevascular that the prevascular carcinoma may be a natural analog to BEC and predicts an intercellular wave connecting the cells., Comment: 9 pages, 4 figures

Extensive Monte Carlo folding simulations for four proteins of various structural classes are carried out, using a single atomistic potential. In all cases, collapse occurs at a very early stage, and proteins fold into their native-like conformations at appropriate temperatures. The results demonstrate that the folding mechanism is controlled not only by thermodynamic factors but also by kinetic factors: The way a protein folds into its native structure, is also determined by the convergence point of early folding trajectories, which cannot be obtained by the free energy surface., Comment: 11 pages, 4 figures

DNA-spools, structures in which DNA is wrapped and helically coiled onto itself or onto a protein core are ubiquitous in nature. We develop a general theory describing the non-equilibrium behavior of DNA-spools under linear tension. Two puzzling and seemingly unrelated recent experimental findings, the sudden quantized unwrapping of nucleosomes and that of DNA toroidal condensates under tension are theoretically explained and shown to be of the same origin. The study provides new insights into nucleosome and chromatin fiber stability and dynamics.

We present a theory to investigate electro-kinetic behavior, namely, electrorotation and dielectrophoresis under alternating current (AC) applied fields for a pair of touching inhomogeneous colloidal particles and biological cells. These inhomogeneous particles are treated as graded ones with physically motivated model dielectric and conductivity profiles. The mutual polarization interaction between the particles yields a change in their respective dipole moments, and hence in the AC electrokinetic spectra. The multipolar interactions between polarized particles are accurately captured by the multiple images method. In the point-dipole limit, our theory reproduces the known results. We find that the multipolar interactions as well as the spatial fluctuations inside the particles can affect the AC electrokinetic spectra significantly., Comment: Revised version with minor changes: References added and discussion extended

Mechanical coupling between a cell and substrate relies on focal adhesions, clusters of adhesion proteins linking stress fibers (bundles of actin proteins) inside the cell with surrounding tissue. Focal adhesions have been demonstrated to both measure and regulate the mechanical traction along the stress fibers. We present a quantitative model for focal adhesion mechano-sensing and stress regulation based on stress amplification at the critical point of a condensation transition of the adhesion proteins., Comment: 4 pages, 2 figures

We present a generic model for DNA at the base-pair level. We use a variant of the Gay-Berne potential to represent the stacking energy between neighboring base-pairs. The sugar-phosphate backbones are taken into account by semi-rigid harmonic springs with a non-zero spring length. The competition of these two interactions and the introduction of a simple geometrical constraint leads to a stacked right-handed B-DNA-like conformation. The mapping of the presented model to the Marko-Siggia and the Stack-of-Plates model enables us to optimize the free model parameters so as to reproduce the experimentally known observables such as persistence lengths, mean and mean squared base-pair step parameters. For the optimized model parameters we measured the critical force where the transition from B- to S-DNA occurs to be approximately $140{pN}$. We observe an overstretched S-DNA conformation with highly inclined bases that partially preserves the stacking of successive base-pairs., Comment: 15 pages, 25 figures. submitted to PRE

Understanding of the evolutionary origins of protein structures represents a key component of the understanding of molecular evolution as a whole. Here we seek to elucidate how the features of an underlying protein structural "space" might impact protein structural evolution. We approach this question using lattice polymers as a completely characterized model of this space. We develop a measure of structural comparison of lattice structures that is analgous to the one used to understand structural similarities between real proteins. We use this measure of structural relatedness to create a graph of lattice structures and compare this graph (in which nodes are lattice structures and edges are defined using structural similarity) to the graph obtained for real protein structures. We find that the graph obtained from all compact lattice structures exhibits a distribution of structural neighbors per node consistent with a random graph. We also find that subgraphs of 3500 nodes chosen either at random or according to physical constraints also represent random graphs. We develop a divergent evolution model based on the lattice space which produces graphs that, within certain parameter regimes, recapitulate the scale-free behavior observed in similar graphs of real protein structures., Comment: 27 pages, 7 figures

Experimental observations suggest that proteins follow different pathways under different environmental conditions. We perform molecular dynamics simulations of a model of the SH3 domain over a broad range of temperatures, and identify distinct pathways in the folding transition. We determine the kinetic partition temperature --the temperature for which the SH3 domain undergoes a rapid folding transition with minimal kinetic barriers-- and observe that below this temperature the model protein may undergo a folding transition via multiple folding pathways. The folding kinetics is characterized by slow and fast pathways and the presence of only one or two intermediates. Our findings suggest the hypothesis that the SH3 domain, a protein for which only two-state folding kinetics was observed in previous experiments, may exhibit intermediates states under extreme experimental conditions, such as very low temperatures. A very recent report (Viguera et al., Proc. Natl. Acad. Sci. USA, 100:5730--5735, 2003) of an intermediate in the folding transition of the Bergerac mutant of the alpha-spectrin SH3 domain protein supports this hypothesis., Comment: 16 pages, 4 figures To be published in the "Journal of Molecular Biology"

Several controversial issues concerning the packing of linear DNA in bacteriophages and globules are discussed. Exact relations for the osmotic pressure, capsid pressure and loading force are derived in terms of the hole size inside phages under the assumption that the DNA globule has a uniform density. A new electrostatic model is introduced for computing the osmotic pressure of rodlike polyelectrolytes at very high concentrations. At intermediate packing, a reptation model is considered for DNA diffusing within a toroidal globule. Under tight packing conditions, a model of Coulomb sliding friction is proposed. A general discussion is given of our current understanding of the statics and dynamics of confined DNA in the context of to the following experiments: characterization of the liquid crystalline phases, X-ray scattering by phages, osmotic stress measurements, cyclization within globules and single-molecule determination ofthe loading forces., Comment: 32 pages, 5 figures, submitted to Phil.Trans.Roy.Soc.A ; special issue entitled "Mechanics of DNA", editor J.M.T.Thompson

A jump-diffusion process is proposed to describe the displacements performed by single myosin heads along actin filaments during the rising phases. The process consists of the superposition of a Wiener and a jump process, with jumps originated by sequences of Poisson-distributed energy-supplying pulses. In a previous paper, the amplitude of the jumps was described by a mixture of two Gaussian distributions. To embody the effects of ATP hydrolysis, we now refine such a model by assuming that the jumps' amplitude is described by a mixture of three Gaussian distributions. This model has been inspired by the experimental data of T. Yanagida and his co-workers concerning observations at single molecule processes level., Comment: 9 pages, 4 figures

The formation of local denaturation zones (bubbles) in double-stranded DNA is an important example for conformational changes of biological macromolecules. We study the dynamics of bubble formation in terms of a Fokker-Planck equation for the probability density to find a bubble of size n base pairs at time t, on the basis of the free energy in the Poland-Scheraga model. Characteristic bubble closing and opening times can be determined from the corresponding first passage time problem, and are sensitive to the specific parameters entering the model. A multistate unzipping model with constant rates recently applied to DNA breathing dynamics [G. Altan-Bonnet et al, Phys. Rev. Lett. 90, 138101 (2003)] emerges as a limiting case., Comment: 9 pages, 2 figures

We present a temperature-independent Monte Carlo method for the determination of the density of states of lattice proteins that combines the fast ground-state search strategy of the nPERM chain growth and multicanonical reweighting for sampling the complete energy space. Since the density of states contains all energetic information of a statistical system, we can directly calculate the mean energy, specific heat, Gibbs free energy, and entropy for all temperatures. We apply this method to HP lattice proteins and for the examples of sequences considered, we identify the transitions between native, globule, and random coil states. Since no special properties of heteropolymers are involved in this algorithm, the method applies to polymer models as well., Comment: 4 pages, RevTeX, 5 Postscript figures, Author Information under http://www.physik.uni-leipzig.de/CQT

Physical mechanisms underlying the empirical correlation between relative contact order (CO) and folding rate among naturally-occurring small single-domain proteins are investigated by evaluating postulated interaction schemes for a set of three-dimensional 27mer lattice protein models with 97 different CO values. Many-body interactions are constructed such that contact energies become more favorable when short chain segments sequentially adjacent to the contacting residues adopt native-like conformations. At a given interaction strength, this scheme leads to folding rates that are logarithmically well correlated with CO (correlation coefficient $r=0.914$) and span more than 2.5 orders of magnitude, whereas folding rates of the corresponding G\=o models with additive contact energies have much less logarithmic correlation with CO and span only approximately one order of magnitude. The present protein chain models also exhibit calorimetric cooperativity and linear chevron plots similar to that observed experimentally for proteins with apparent simple two-state folding/unfolding kinetics. Thus, our findings suggest that CO-dependent folding rates of real proteins may arise partly from a significant positive coupling between nonlocal contact favorabilities and local conformational preferences., Comment: 23 pages, 4 postscript figures (will appear on Proteins)

The immunological synapse is a patterned collection of different types of receptors and ligands that forms in the intercellular junction between T Cells and antigen presenting cells (APCs) during recognition. The synapse is implicated in information transfer between cells, and is characterized by different spatial patterns of receptors at different stages in the life cycle of T cells. We obtain a minimalist model that captures this experimentally observed phenomenology. A functional RG analysis provides further insights., Comment: 6 pages, 3 figures, submitted for publication

The curvature stress of DNA packed inside a phage is balanced against its electrostatic self-interaction. The DNA density is supposed nonuniform and as a result the Donnan effect is also inhomogeneous. The coarse-grained DNA density is a nonlinear function of the DNA radius of curvature at a given position inside the bacteriophage. It turns out that a region (or regions) exists totally free from DNA. The size of such holes is computed., Comment: 11 pages, 2 figures, submitted to J. Phys. Chem. B (special Polyelectrolytes issue)

In the framework of the Poland Scheraga model of DNA denaturation, we derive a recursion relation for the partition function of double stranded DNA, allowing for mismatches between the two strands. This relation is studied numerically using standard parameters for the stacking energies and loop entropies. For complementary strands (of length 1000), we find that mismatches are significant only when the cooperativity parameter $\sigma$ is of order one. Since $\sigma \sim O(10^{-5})$ in DNA, entropic gains from mismatches are overwhelmed by the energetic cost of opening a loop: mismatches are therefore irrelevant (and molecular recognition of the strands is perfect). Generating random mutations with probability $p$ on one strand, we find that large values of $\sigma$ are rather tolerant to mutations. For realistic (small) values of $\sigma$, the two strands do not recombine, even for small mutation fractions. Thus, molecular recognition is extremely selective., Comment: 7 pages, uses epl.cls (included), a few typos corrected

We address theoretically aggregation of DNA segments by multivalent polyamines such as spermine and spermidine. In experiments, the aggregation occurs above a certain threshold concentration of multivalent ions. We demonstrate that the dependence of this threshold on the concentration of DNA has a simple form. When the DNA concentration c_DNA is smaller than the monovalent salt concentration, the threshold multivalent ion concentration depends linearly on c_DNA, having the form alpha c_DNA + beta. The coefficients alpha and beta are related to the density profile of multivalent counterions around isolated DNA chains, at the onset of their aggregation. This analysis agrees extremely well with recent detailed measurements on DNA aggregation in the presence of spermine. From the fit to the experimental data, the number of condensed multivalent counterions per DNA chain can be deduced. A few other conclusions can then be reached: i) the number of condensed spermine ions at the onset of aggregation decreases with the addition of monovalent salt; ii) the Poisson-Boltzmann theory over-estimates the number of condensed multivalent ions at high monovalent salt concentrations; iii) our analysis of the data indicates that the DNA charge is not over-compensated by spermine at the onset of aggregation., Comment: 12 pages, 8 figures. Biophysical Journal 2003, in press

A lattice model of RNA denaturation which fully accounts for the excluded volume effects among nucleotides is proposed. A numerical study shows that interactions forming pseudoknots must be included in order to get a sharp continuous transition. Otherwise a smooth crossover occurs from the swollen linear polymer behavior to highly ramified, almost compact conformations with secondary structures. In the latter scenario, which is appropriate when these structures are much more stable than pseudoknot links, probability distributions for the lengths of both loops and main branches obey scaling with nonclassical exponents., Comment: 4 pages 3 figures

The electrodynamic response of DNA in the millimeter wave range is investigated. By performing measurements under a wide range of humidity conditions and comparing the response of single strand DNA and double strand DNA, we show that the appreciable AC conductivity of DNA is not due to photon activated hopping between localized states, but instead due to dissipation from dipole motion in the surrounding water helix. Such a result, where the conductivity is due to the constrained motion of overdamped dipoles, reconciles the vanishing DC conductivity of DNA with the considerable AC response., Comment: 4 pages, 3 figures

It is shown that the scaling analysis presented in Phys. Rev. Lett. 85, 4988 (2000) is valid for finite chains of lengths relevant to experiments, in contrast to a recent claim made by A. Hanke and R. Metzler in cond-mat/0110164.

We study an off-lattice protein toy model with two species of monomers interacting through modified Lennard-Jones interactions. Low energy configurations are optimized using the pruned-enriched-Rosenbluth method (PERM), hitherto employed to native state searches only for off lattice models. For 2 dimensions we found states with lower energy than previously proposed putative ground states, for all chain lengths $\ge 13$. This indicates that PERM has the potential to produce native states also for more realistic protein models. For $d=3$, where no published ground states exist, we present some putative lowest energy states for future comparison with other methods., Comment: 4 pages, 2 figures

Simple two-state folding kinetics of many small single-domain proteins are characterized by chevron plots with linear folding and unfolding arms consistent with a two-state description of equilibrium thermodynamics. This phenomenon is hereby recognized as a nontrivial heteropolymer property capable of providing fundamental insight into protein energetics. Many current protein chain models, including common lattice and continuum G\=o models with explicit native biases, fail to reproduce this generic protein property. Here we show that simple two-state kinetics is obtainable from models with a cooperative interplay between core burial and local conformational propensities or an extra strongly favorable energy for the native structure. These predictions suggest that intramolecular recognition in real two-state proteins is more specific than that envisioned by common G\=o-like constructs with pairwise additive energies. The many-body interactions in the present kinetically two-state models lead to high thermodynamic cooperativity as measured by their van't Hoff to calorimetric enthalpy ratios, implying that the native and denatured conformational populations are well separated in enthalpy by a high free energy barrier. Consistent with experiments, comparison among the present models with extra native favorabilities indicate that their folding rate at a given interaction strength decreases with increasing native contact order, although the dependence is weaker than the corresponding trend in real proteins. It has been observed experimentally that deviations from Arrhenius behavior are often more severe for folding than for unfolding. This asymmetry may be rationalized by one ..., Comment: 30 pages, 8 Postscript figures (will appear in Proteins)

Chevron rollovers of some proteins imply that their logarithmic folding rates are nonlinear in native stability. This is predicted by lattice and continuum G\=o models to arise from diminished accessibilities of the ground state from transiently populated compact conformations under strongly native conditions. Despite these models' native-centric interactions, the slowdown is due partly to kinetic trapping caused by some of the folding intermediates' nonnative topologies. Notably, simple two-state folding kinetics of small single-domain proteins are not reproduced by common G\=o-like schemes., Comment: 10 pages, 4 Postscript figures (will appear on PRL)

We calculate the induced elastic-interaction between pointwise membrane inclusions that locally interact up to quadratic order with the membrane curvature tensor. For isotropic inclusions, we recover the usual interaction proportional to the inverse fourth power of the separation, however with a prefactor showing a non-trivial dependence on the rigidity $\Gamma$ of the quadratic potential. In the large $\Gamma$ limit, corresponding to ``hard'' inclusions, we recover the standard prefactor first obtained by Goulian et al. [Europhys. Lett. \textbf{22}, 145 (1993)]. In the small $\Gamma$ limit, corresponding to "soft" inclusions, we recover the recent result of Marchenko and Misbah [Eur. Phys. J. E \textbf{8}, 477 (2002)]. This shows that the latter result bears no fundamental discrepancy with previous works, but simply corresponds to the limit of soft inclusions. We discuss how the same inclusion can be depicted as hard or soft according to the degree of coarse-graining of the pointwise description. Finally, we argue that conical transmembrane proteins should be fundamentally considered as hard inclusions., Comment: 6 pages

We study the spontaneous ''sliding'' of histone spools (nucleosomes) along DNA as a result of thermally activated single base pair twist defects. To this end we map the system onto a suitably extended Frenkel-Kontorova model. Combining results from several recent experiments we are able to estimate the nucleosome mobility without adjustable parameters. Our model shows also how the local mobility is intimately linked to the underlying base pair sequence., Comment: 4 pages, 2 figures

Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which the strands separate rapidly, followed by long pauses where the number of separated base pairs remains constant. Here, we report previously uncharacterized observations of this striking behavior carried out on a number of identical single molecules simultaneously. When several single lphage molecules are subject to the same applied force, the pause positions are reproducible in each. This reproducibility shows that the positions and durations of the pauses in unzipping provide a sequence-dependent molecular fingerprint. For small forces, the DNA remains in a partially unzipped state for at least several hours. For larger forces, the separation is still characterized by jumps and pauses, but the double-stranded DNA will completely unzip in less than 30 min.

Potential functions are critical for computational studies of protein structure prediction, folding, and sequence design. A class of widely used potentials for coarse grained models of proteins are contact potentials in the form of weighted linear sum of pairwise contacts. However, these potentials have been shown to be unsuitable choices because they cannot stabilize native proteins against a large number of decoys generated by gapless threading. We develop an alternative framework for designing protein potential. We describe how finding optimal protein potential can be understood from two geometric viewpoints, and we derive nonlinear potentials using mixture of Gaussian kernel functions for folding and design. The optimization criterion for obtaining parameters of the potential is to minimize bounds on the generalization error of discriminating protein structures and decoys not used in training. In our experiment we use a training set of 440 protein structures repre senting a major portion of all known protein structures, and about 14 million structure decoys and sequence decoys obtained by gapless threading. We succeeded in obtaining nonlinear potential with perfect discrimination of the 440 native structures and native sequences. For the more challenging task of sequence design when decoys are obtained by gapless threading, we show that there is no linear potential with perfect discrimination of all 440 native sequences. Results on an independent test set of 194 proteins also showed that nonlinear kernel potential performs well., Comment: 22 pages, 7 figures, and 5 tables

The results of minimal model calculations suggest that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By mean of molecular dynamics simulations around the native conformation, which simulate the protein and the surrounding solvent at full--atom level, we generate an energetic map of the equilibrium state of the protein and simplify it with an Eigenvalue decomposition. The components of the Eigenvector associated with the lowest Eigenvalue indicate which are the "hot" sites responsible for the stability and for the fast folding of the protein. Comparison of these predictions with the results of mutatgenesis experiments, performed for five small proteins, provide an excellent agreement.

The translocation of a macromolecule through a nanometer-sized pore is an interesting process with important applications in the development of biosensors for single--molecule analysis and in drug delivery and gene therapy. We have carried out a molecular dynamics simulation study of electrophoretic translocation of a charged polymer through an artificial nanopore to explore the feasibility of semiconductor--based nanopore devices for ultra--fast DNA sequencing. The polymer is represented by a simple bead--spring model designed to yield an appropriate coarse-grained description of the phosphate backbone of DNA in salt--free aqueous solution. A detailed analysis of single translocation event is presented to assess whether the passage of individual ions through the pore can be detected by a nanoscale field--effect transistor by measuring variations in electrostatic potential during polymer translocation. We find that it is possible to identify single events corresponding to the passage of counterions through the pore, but that discrimination of individual ions on the polymer chain based on variations in electrostatic potential is problematic. Several distinct stages in the translocation process are identified, characterized by changes in polymer conformation and by variations in the magnitude and direction of the internal electric field induced by the fluctuating charge distribution. The dependence of the condensed fraction of counterions on Bjerrum length leads to significant changes in polymer conformation, which profoundly affect the dynamics of electrophoresis and translocation., Comment: 37 pages Revtex, 11 postscript figures

The coding sequence in DNA molecule is considered as a message to be transferred to receiver, the proteins, through a noisy information channel and each nucleotide is assigned a respective information weight. With the help of the nucleotide substitution matrix we estimated the lower bound of the amount of information carried out by nucleotides which is not subject of mutations. We used the calculated weights to reconstruct k-oligomers of genes from the Borrelia burgdorferi genome. We showed, that to this aim there is sufficient a simple rule, that the number of bits of the carried information cannot exceed some threshold value. The method introduced by us is general and applies to every genome., Comment: 8 pages, 7 figures, submitted for publication

Recent structural findings have shown that dynamin, a cytosol protein playing a key-role in clathrin-mediated endocytosis, inserts partly within the lipid bilayer and tends to self-assemble around lipid tubules. Taking into account these observations, we make the hypothesis that individual membrane inserted dynamins imprint a local cylindrical curvature to the membrane. This imprint may give rise to long-range mechanical forces mediated by the elasticity of the membrane. Calculating the resulting many-body interaction between a collection of inserted dynamins and a membrane bud, we find a regime in which the dynamins are elastically recruited by the bud to form a collar around its neck, which is reminiscent of the actual process preempting vesicle scission. This physical mechanism might therefore be implied in the recruitment of dynamins by clathrin coats., Comment: 11 pages, 6 figures, to appear in C.R.A.S. ser III

Motivated by recent experiments on DNA torsion-force-extension characteristics we consider the writhing geometry of open stiff molecules. We exhibit a cyclic motion which allows arbitrarily large twisting of the end of a molecule via an activated process. This process is suppressed for forces larger than femto-Newtons which allows us to show that experiments are sensitive to a generalization of the Calugareanu-White formula for the writhe. Using numerical methods we compare this formulation of the writhe with recent analytic calculations., Comment: 12 pages 10 figures. Revtex4

A framework is presented for understanding the common character of proteins. Proteins are linear chain molecules. However, the simple model of a polymer viewed as spheres tethered together does not account for many of the observed characteristics of protein structures. The authors show here that proteins may be regarded as tubes of nonzero thickness. This approach allows one to bridge the conventional compact polymer phase with a novel phase employed by Nature to house biomolecular structures. The continuum description of a tube (or a sheet) of arbitrary thickness entails using appropriately chosen many-body interactions rather than two-body interactions. The authors suggest that the structures of folded proteins are selected based on geometrical considerations and are poised at the edge of compaction, thus accounting for their versatility and flexibility. This approach also offers an explanation for why helices and sheets are the building blocks of protein structures., Comment: 30 pages, 5 figures

We study a physical model for the interaction between general inclusions bound to fluid membranes that possess finite tension, as well as the usual bending rigidity. We are motivated by an interest in proteins bound to cell membranes that apply forces to these membranes, due to either entropic or direct chemical interactions. We find an exact analytic solution for the repulsive interaction between two similar circularly symmetric inclusions. This repulsion extends over length scales of order tens of nanometers, and contrasts with the membrane-mediated contact attraction for similar inclusions on tensionless membranes. For non circularly symmetric inclusions we study the small, algebraically long-ranged, attractive contribution to the force that arises. We discuss the relevance of our results to biological phenomena, such as the budding of caveolae from cell membranes and the striations that are observed on their coats., Comment: 22 pages, 2 figures

We study a physical model for the formation of bud-like invaginations on fluid membranes under tension, and apply this model to caveolae formation. We demonstrate that budding can be driven by membrane-bound inclusions (proteins) provided that they exert asymmetric forces on the membrane that give rise to bending moments. In particular, Caveolae formation may not necessarily require forces to be applied by the cytoskeleton. Our theoretical model is able to explain several features observed experimentally in caveolae, where proteins in the caveolin family are known to play a crucial role in the formation of caveolae buds. These include (i) the formation of caveolae buds with sizes in the 100nm range (ii) that a fairly large variation of bud shape is expected (iii) that certain N and C termini deletion mutants result in vesicles that are an order of magnitude larger. Finally, we discuss the possible origin of the morphological striations that are observed on the surfaces of the caveolae., Comment: 18 pages, 3 figures

Single domain proteins are thought to be tightly packed. The introduction of voids by mutations is often regarded as destabilizing. In this study we show that packing density for single domain proteins decreases with chain length. We find that the radius of gyration provides poor description of protein packing but the alpha contact number we introduce here characterize proteins well. We further demonstrate that protein-like scaling relationship between packing density and chain length is observed in off-lattice self-avoiding walks. A key problem in studying compact chain polymer is the attrition problem: It is difficult to generate independent samples of compact long self-avoiding walks. We develop an algorithm based on the framework of sequential Monte Carlo and succeed in generating populations of compact long chain off-lattice polymers up to length $N=2,000$. Results based on analysis of these chain polymers suggest that maintaining high packing density is only characteristic of short chain proteins. We found that the scaling behavior of packing density with chain length of proteins is a generic feature of random polymers satisfying loose constraint in compactness. We conclude that proteins are not optimized by evolution to eliminate packing voids., Comment: 9 pages, 10 figures. Accepted by J. Chem. Phys

We study cold denaturation of proteins at high pressures. Using multicanonical Monte Carlo simulations of a model protein in a water bath, we investigate the effect of water density fluctuations on protein stability. We find that above the pressure where water freezes to the dense ice phase ($\approx2$ kbar), the mechanism for cold denaturation with decreasing temperature is the loss of local low-density water structure. We find our results in agreement with data of bovine pancreatic ribonuclease A., Comment: 4 pages for double column and single space. 3 figures Added references Changed content

The dynamics of polymer translocation through a pore has been the subject of recent theoretical and experimental works. We have considered theoretical estimates and performed computer simulations to understand the mechanism of DNA uptake into the cell nucleus, a phenomenon experimentally investigated by attaching a small bead to the free end of the double helix and pulling this bead with the help of an optical trap. The experiments show that the uptake is monotonous and slows down when the remaining DNA segment becomes very short. Numerical and analytical studies of the entropic repulsion between the DNA filament and the membrane wall suggest a new interpretation of the experimental observations. Our results indicate that the repulsion monotonically decreases as the uptake progresses. Thus, the DNA is pulled in (i) either by a small force of unknown origin, and then the slowing down can be interpreted only statistically; (ii) or by a strong but slow ratchet mechanism, which would naturally explain the observed monotonicity, but then the slowing down requires additional explanations. Only further experiments can unambiguously distinguish between these two mechanisms., Comment: 12 pages, 6 figures, submitted to J. Phys. Cond. Mat

Because the constant extension ensemble of single chain molecule is not always equivalent with constant force ensemble, a model of double-stranded conformations, as in RNA molecules and $\beta$-sheets in proteins, with fixed extension constraint is built in this paper. Based on polymer-graph theory and the self-avoiding walks, sequence dependence and excluded-volume interactions are explicitly taken into account. Using the model, we investigate force-extension curves, contact distributions and force-temperature curves at given extensions. We find that, for the same homogeneous chains, the force-extension curves are almost consistent with the extension-force curves in the conjugated force ensembles. Especially, the consistence depends on chain lengths. But the curves of the two ensembles are completely different from each other if sequences are considered. In addition, contact distributions of homogeneous sequence show that the double-stranded regions in hairpin conformations tend to locate at two sides of the chain. We contribute the unexpected phenomena to the nonuniformity of excluded-volume interactions of the region and two tails with different lengths. This tendency will disappear if the interactions are canceled. Finally, in constant extension ensemble, the force-flipping transitions conjugated with re-entering phenomena in constant force ensemble are observed in hairpin conformations, while they do not present in secondary structure conformations., Comment: 15 pages, 24 figures

The dynamics of contact pair formation between various hydrophobic residues during folding of a model protein Hp-36 is investigated by Brownian dynamics simulation. Hydropathy scale and non-local helix propensity of amino acids are used to model the complex interaction potential. The resulting structure of the model protein mimics the native state of the real protein with a $RMSD$ of 4.5 \AA. A contact pair distance time correlation function (CPCF), $C_{P}^{ij}(t)$, is introduced which shows multistage decay, including a {\it slow late stage dynamics} for a few specific pairs. {\it These pairs determine the long time folding rate}. Dynamics can be correlated with the landscape, relative contact order and topological contact., Comment: 4 pages including 4 figures. Submitted to the Phys. Rev. Lett

We modify and extend the recently developed statistical mechanical model for predicting the thermodynamic properties of chain molecules having noncovalent double-stranded conformations, as in RNA or ssDNA, and $\beta-$sheets in protein, by including the constant force stretching at one end of molecules as in a typical single-molecule experiment. The conformations of double-stranded regions of the chain are calculated based on polymer graph-theoretic approach [S-J. Chen and K. A. Dill, J. Chem. Phys. {\bf109}, 4602(1998)], while the unpaired single-stranded regions are treated as self-avoiding walks. Sequence dependence and excluded volume interaction are taken into account explicitly. Two classes of conformations, hairpin and RNA secondary structure are explored. For the hairpin conformations, all possible end-to-end distances corresponding to the different types of double-stranded regions are enumerated exactly. For the RNA secondary structure conformations, a new recursive formula incorporating the secondary structure and end-to-end distribution has been derived. Using the model, we investigate the extension-force curves, contact and population distributions and re-entering phenomena, respectively. we find that the force stretching homogeneous chains of hairpin and secondary structure conformations are very different: the unfolding of hairpins is two-state, while unfolding the latter is one-state. In addition, re-entering transitions only present in hairpin conformations, but are not observed in secondary structure conformations., Comment: 19 pages, 28 figures