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At least 19 recordsLinked to original sources

arXiv2006

Solitons in a double pendulums chain model, and DNA roto-torsional dynamics

It was first suggested by Englander et al to model the nonlinear dynamics of DNA relevant to the transcription process in terms of a chain of coupled pendulums. In a related paper [q-bio.BM/0604014] we argued for the advantages of an extension of this approach based on considering a chain of double pendulums with certain characteristics. Here we study a simplified model of this kind, focusing on its general features and nonlinear travelling wave excitations; in particular, we show that some of the degrees of freedom are actually slaved to others, allowing for an effective reduction of the relevant equations.

q-bio.BM↗

arXiv2014

Characterizing the folding core of the cyclophilin A - cyclosporin A complex I: hydrogen exchange data and rigidity analysis

The determination of a 'folding core' can help to provide insight into the structure, flexibility, mobility and dynamics, and hence, ultimately, function of a protein - a central concern of structural biology. Changes in the folding core upon ligand binding are of particular interest because they may be relevant to drug-induced functional changes. Cyclophilin A is a multi-functional ligand-binding protein and a significant drug target. It acts principally as an enzyme during protein folding, but also as the primary binding partner for the immunosuppressant drug cyclosporin A (CsA). Here, we have used hydrogen-deuterium exchange (HDX) NMR spectroscopy to determine the folding core of the CypA-CsA complex. We also use the rapid computational tool of rigidity analysis, implemented in FIRST, to determine a theoretical folding core of the complex. In addition we generate a theoretical folding core for the unbound protein and compare this with previously published HDX data. The FIRST method gives a good prediction of the HDX folding core, but we find that it is not yet sufficiently sensitive to predict the effects of ligand binding on CypA.

q-bio.BM↗

arXiv2013

Charge transfer along DNA dimers, trimers and polymers

The transfer of electrons and holes along DNA dimers, trimers and polymers is described at the base-pair level, using the relevant on-site energies of the base-pairs and the hopping parameters between successive base-pairs. The temporal and spatial evolution of carriers along a $N$ base-pair DNA segment is determined, solving a system of $N$ coupled differential equations. Useful physical quantities are calculated including the pure mean carrier transfer rate $k$, the inverse decay length $β$ used for exponential fit ($k = k_0 \textrm{exp}(-βd)$) of the transfer rate as a function of the charge transfer distance $d = N \times$ 3.4 Å and the exponent $η$ used for a power law fit ($k = k_0' N^{-η}$) of the transfer rate as function of the number of monomers $N$. Among others, the electron and hole transfer along the polymers poly(dG)-poly(dC), poly(dA)-poly(dT), GCGCGC..., ATATAT... is studied. $β$ ($η$) falls in the range $\approx$ 0.2 - 2 Å$^{-1}$ (1.7 - 17), $k_0$ ($k_0'$) is usually $\approx 10^{-2}$-10$^{-1}$ ($ 10^{-2}$-10$^{-1}$) PHz although, generally, it falls in the wider range $\approx 10^{-4}$-10 ($10^{-4}$-10$^3$) PHz. The results are compared with past predictions and experiments. Our approach illustrates to which extent a specific DNA segment can serve as an efficient medium for charge transfer.

physics.bio-ph↗

arXiv2008

Sensitivity of protein rigidity analysis to small structural variations: a large-scale comparative analysis

Rigidity analysis using the "pebble game" can usefully be applied to protein crystal structures to obtain information on protein folding, assembly and the structure-function relationship. However, previous work using this technique has not made clear how sensitive rigidity analysis is to small structural variations. We present a comparative study in which rigidity analysis is applied to multiple structures, derived from different organisms and different conditions of crystallisation, for each of several different proteins. We find that rigidity analysis is best used as a comparative tool to highlight the effects of structural variation. Our use of multiple protein structures brings out a previously unnoticed peculiarity in the rigidity of trypsin.

q-bio.MN↗

arXiv2011

An optimization strategy on prion AGAAAAGA amyloid fibril molecular modeling

X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy are two powerful tools to determine the protein 3D structure. However, not all proteins can be successfully crystallized, particularly for membrane proteins. Although NMR spectroscopy is indeed very powerful in determining the 3D structures of membrane proteins, same as X-ray crystallography, it is still very time-consuming and expensive. Under many circumstances, due to the noncrystalline and insoluble nature of some proteins, X-ray and NMR cannot be used at all. Computational approaches, however, allow us to obtain a description of the protein 3D structure at a submicroscopic level. To the best of the author's knowledge, there is little structural data available to date on the AGAAAAGA palindrome in the hydrophobic region (113--120) of prion proteins, which falls just within the N-terminal unstructured region (1--123) of prion proteins. Many experimental studies have shown that the AGAAAAGA region has amyloid fibril forming properties and plays an important role in prion diseases. However, due to the noncrystalline and insoluble nature of the amyloid fibril, little structural data on the AGAAAAGA is available. This paper introduces a simple optimization strategy approach to address the 3D atomic-resolution structure of prion AGAAAAGA amyloid fibrils. Atomic-resolution structures of prion AGAAAAGA amyloid fibrils got in this paper are useful for the drive to find treatments for prion diseases in the field of medicinal chemistry.

cs.CE↗

arXiv2007

Intricate Knots in Proteins: Function and Evolution

A number of recently discovered protein structures incorporate a rather unexpected structural feature: a knot in the polypeptide backbone. These knots are extremely rare, but their occurrence is likely connected to protein function in as yet unexplored fashion. Our analysis of the complete Protein Data Bank reveals several new knots which, along with previously discovered ones, can shed light on such connections. In particular, we identify the most complex knot discovered to date in human ubiquitin hydrolase, and suggest that its entangled topology protects it against unfolding and degradation by the proteasome. Knots in proteins are typically preserved across species and sometimes even across kingdoms. However, we also identify a knot which only appears in some transcarbamylases while being absent in homologous proteins of similar structure. The emergence of the knot is accompanied by a shift in the enzymatic function of the protein. We suggest that the simple insertion of a short DNA fragment into the gene may suffice to turn an unknotted into a knotted structure in this protein.

physics.bio-ph↗

arXiv2007

A Finite Element framework for computation of protein normal modes and mechanical response

A coarse-grained computational procedure based on the Finite Element Method is proposed to calculate the normal modes and mechanical response of proteins and their supramolecular assemblies. Motivated by the elastic network model, proteins are modeled as homogeneous isotropic elastic solids with volume defined by their solvent-excluded surface. The discretized Finite Element representation is obtained using a surface simplification algorithm that facilitates the generation of models of arbitrary prescribed spatial resolution. The procedure is applied to compute the normal modes of a mutant of T4 phage lysozyme and of filamentous actin, as well as the critical Euler buckling load of the latter when subject to axial compression. Results compare favorably with all-atom normal mode analysis, the Rotation Translation Blocks procedure, and experiment. The proposed methodology establishes a computational framework for the calculation of protein mechanical response that facilitates the incorporation of specific atomic-level interactions into the model, including aqueous-electrolyte-mediated electrostatic effects. The procedure is equally applicable to proteins with known atomic coordinates as it is to electron density maps of proteins, protein complexes, and supramolecular assemblies of unknown atomic structure.

q-bio.BM↗

arXiv2007

Observation of Multiple folding Pathways of beta-hairpin Trpzip2 from Independent Continuous Folding Trajectories

We report 10 successfully folding events of trpzip2 by molecular dynamics simulation. It is found that the trizip2 can fold into its native state through different zipper pathways, depending on the ways of forming hydrophobic core. We also find a very fast non-zipper pathway. This indicates that there may be no inconsistencies in the current pictures of beta-hairpin folding mechanisms. These pathways occur with different probabilities. zip-out is the most probable one. This may explain the recent experiment that the turn formation is the rate-limiting step for beta-hairpin folding.

q-bio.BM↗

arXiv2007

Fourier Analysis of Biological Evolution: Concept of Selection Moment

Secondary structure elements of many protein families exhibit differential conservation on their opposing faces. Amphipathic helices and beta-sheets by definition possess this property, and play crucial functional roles. This type of evolutionary trajectory of a protein family is usually critical to the functions of the protein family, as well as in creating functions within subfamilies. That is, differential conservation maintains properties of a protein structure related to its orientation, and that are important in packing, recognition, and catalysis. Here I define and formulate a new concept, called the selection moment, that detects this evolutionary process in protein sequences. A treatment of its various applications is detailed.

q-bio.BM↗

arXiv2007

Network Structure of Protein Folding Pathways

The classical approach to protein folding inspired by statistical mechanics avoids the high dimensional structure of the conformation space by using effective coordinates. Here we introduce a network approach to capture the statistical properties of the structure of conformation spaces. Conformations are represented as nodes of the network, while links are transitions via elementary rotations around a chemical bond. Self-avoidance of a polypeptide chain introduces degree correlations in the conformation network, which in turn lead to energy landscape correlations. Folding can be interpreted as a biased random walk on the conformation network. We show that the folding pathways along energy gradients organize themselves into scale free networks, thus explaining previous observations made via molecular dynamics simulations. We also show that these energy landscape correlations are essential for recovering the observed connectivity exponent, which belongs to a different universality class than that of random energy models. In addition, we predict that the exponent and therefore the structure of the folding network fundamentally changes at high temperatures, as verified by our simulations on the AK peptide.

q-bio.BM↗

arXiv2007

A three-state prediction of single point mutations on protein stability changes

A basic question of protein structural studies is to which extent mutations affect the stability. This question may be addressed starting from sequence and/or from structure. In proteomics and genomics studies prediction of protein stability free energy change (DDG) upon single point mutation may also help the annotation process. The experimental SSG values are affected by uncertainty as measured by standard deviations. Most of the DDG values are nearly zero (about 32% of the DDG data set ranges from -0.5 to 0.5 Kcal/mol) and both the value and sign of DDG may be either positive or negative for the same mutation blurring the relationship among mutations and expected DDG value. In order to overcome this problem we describe a new predictor that discriminates between 3 mutation classes: destabilizing mutations (DDG<-0.5 Kcal/mol), stabilizing mutations (DDG>0.5 Kcal/mol) and neutral mutations (-0.5<=DDG<=0.5 Kcal/mol). In this paper a support vector machine starting from the protein sequence or structure discriminates between stabilizing, destabilizing and neutral mutations. We rank all the possible substitutions according to a three state classification system and show that the overall accuracy of our predictor is as high as 52% when performed starting from sequence information and 58% when the protein structure is available, with a mean value correlation coefficient of 0.30 and 0.39, respectively. These values are about 20 points per cent higher than those of a random predictor.

q-bio.BM↗

arXiv2007

In silico evidence of the relationship between miRNAs and siRNAs

Both short interfering RNAs (siRNAs) and microRNAs (miRNAs) mediate the repression of specific sequences of mRNA through the RNA interference pathway. In the last years several experiments have supported the hypothesis that siRNAs and miRNAs may be functionally interchangeable, at least in cultured cells. In this work we verify that this hypothesis is also supported by a computational evidence. We show that a method specifically trained to predict the activity of the exogenous siRNAs assigns a high silencing level to experimentally determined human miRNAs. This result not only supports the idea of siRNAs and miRNAs equivalence but indicates that it is possible to use computational tools developed using synthetic small interference RNAs to investigate endogenous miRNAs.

q-bio.BM↗

arXiv2008

DNA Hash Pooling and its Applications

In this paper we describe a new technique for the comparison of populations of DNA strands. Comparison is vital to the study of ecological systems, at both the micro and macro scales. Existing methods make use of DNA sequencing and cloning, which can prove costly and time consuming, even with current sequencing techniques. Our overall objective is to address questions such as: (i) (Genome detection) Is a known genome sequence present, at least in part, in an environmental sample? (ii) (Sequence query) Is a specific fragment sequence present in a sample? (iii) (Similarity discovery) How similar in terms of sequence content are two unsequenced samples? We propose a method involving multiple filtering criteria that result in "pools" of DNA of high or very high purity. Because our method is similar in spirit to hashing in computer science, we call it DNA hash pooling. To illustrate this method, we describe protocols using pairs of restriction enzymes. The in silico empirical results we present reflect a sensitivity to experimental error. Our method will normally be performed as a filtering step prior to sequencing in order to reduce the amount of sequencing required (generally by a factor of 10 or more). Even as sequencing becomes cheaper, an order of magnitude remains important.

q-bio.BM↗

arXiv2007

The Hypercube of Life: How Protein Stability Imposes Limits on Organism Complexity and Speed of Molecular Evolution

Classical population genetics a priori assigns fitness to alleles without considering molecular or functional properties of proteins that these alleles encode. Here we study population dynamics in a model where fitness can be inferred from physical properties of proteins under a physiological assumption that loss of stability of any protein encoded by an essential gene confers a lethal phenotype. Accumulation of mutations in organisms containing Gamma genes can then be represented as diffusion within the Gamma dimensional hypercube with adsorbing boundaries which are determined, in each dimension, by loss of a protein stability and, at higher stability, by lack of protein sequences. Solving the diffusion equation whose parameters are derived from the data on point mutations in proteins, we determine a universal distribution of protein stabilities, in agreement with existing data. The theory provides a fundamental relation between mutation rate, maximal genome size and thermodynamic response of proteins to point mutations. It establishes a universal speed limit on rate of molecular evolution by predicting that populations go extinct (via lethal mutagenesis) when mutation rate exceeds approximately 6 mutations per essential part of genome per replication for mesophilic organisms and 1 to 2 mutations per genome per replication for thermophilic ones. Further, our results suggest that in absence of error correction, modern RNA viruses and primordial genomes must necessarily be very short. Several RNA viruses function close to the evolutionary speed limit while error correction mechanisms used by DNA viruses and non-mutant strains of bacteria featuring various genome lengths and mutation rates have brought these organisms universally about 1000 fold below the natural speed limit.

q-bio.BM↗

arXiv2007

Free-Energy Landscape of Kinesin by a Realistic Lattice Model

Structural fluctuations in the thermal equilibrium of the kinesin motor domain are studied using a lattice protein model with Go interactions. By means of the multi-self-overlap ensemble (MSOE) Monte Carlo method and the principal component analysis (PCA), the free-energy landscape is obtained. It is shown that kinesins have two subdomains that exhibit partial folding/unfolding at functionally important regions: one is located around the nucleotide binding site and the other includes the main microtubule binding site. These subdomains are consistent with structural variability that was reported recently based on experimentally-obtained structures. On the other hand, such large structural fluctuations have not been captured by B-factor or normal mode analyses. Thus, they are beyond the elastic regime, and it is essential to take into account chain connectivity for studying the function of kinesins.

q-bio.BM↗

arXiv2007

Neutral Networks of Sequence to Shape Maps

In this paper we present a novel framework for sequence to shape maps. These combinatorial maps realize exponentially many shapes, and have preimages which contain extended connected subgraphs of diameter n (neutral networks). We prove that all basic properties of RNA folding maps also hold for combinatorial maps. Our construction is as follows: suppose we are given a graph $H$ over the $\{1 >...,n\}$ and an alphabet of nucleotides together with a symmetric relation $\mathcal{R}$, implied by base pairing rules. Then the shape of a sequence of length n is the maximal H subgraph in which all pairs of nucleotides incident to H-edges satisfy $\mathcal{R}$. Our main result is to prove the existence of at least $\sqrt{2}^{n-1}$ shapes with extended neutral networks, i.e. shapes that have a preimage with diameter $n$ and a connected component of size at least $(\frac{1+\sqrt{5}}{2})^n+(\frac{1-\sqrt{5}}{2})^n$. Furthermore, we show that there exists a certain subset of shapes which carries a natural graph structure. In this graph any two shapes are connected by a path of shapes with respective neutral networks of distance one. We finally discuss our results and provide a comparison with RNA folding maps.

q-bio.QM↗

arXiv2007

How do trehalose, maltose and sucrose influence some structural and dynamical properties of lysozyme ? An insight from Molecular Dynamics simulations

The influence of three well-known disaccharides, namely trehalose, maltose and sucrose, on some structural and dynamical properties of lysozyme has been investigated by means of molecular dynamics computer simulations in the 37-60 wt % concentration range. The effects of sugars on the protein conformation are found relatively weak, in agreement with the preferential hydration of lysozyme. Conversely, sugars seem to increase significantly the relaxation times of the protein. These effects are shown to be correlated to the fractional solvent accessibilities of lysozyme residues and further support the slaving of protein dynamics. Moreover, a significant increase in the relaxation times of lysozyme, sugars and water molecules is observed within the studied concentration range and may result from the percolation of the hydrogen-bond network of sugar molecules. This percolation appears to be of primary importance to explain the influence of sugars on the dynamical properties of lysozyme and water.

physics.chem-ph↗

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↗