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Publication# Looping probabilities of elastic chains: A path integral approach

Abstract

We consider an elastic chain at thermodynamic equilibrium with a heat bath, and derive an approximation to the probability density function, or pdf, governing the relative location and orientation of the two ends of the chain. Our motivation is to exploit continuum mechanics models for the computation of DNA looping probabilities, but here we focus on explaining the novel analytical aspects in the derivation of our approximation formula. Accordingly, and for simplicity, the current presentation is limited to the illustrative case of planar configurations. A path integral formalism is adopted, and, in the standard way, the first approximation to the looping pdf is obtained from a minimal energy configuration satisfying prescribed end conditions. Then we compute an additional factor in the pdf which encompasses the contributions of quadratic fluctuations about the minimum energy configuration along with a simultaneous evaluation of the partition function. The original aspects of our analysis are twofold. First, the quadratic Lagrangian describing the fluctuations has cross-terms that are linear in first derivatives. This, seemingly small, deviation from the structure of standard path integral examples complicates the necessary analysis significantly. Nevertheless, after a nonlinear change of variable of Riccati type, we show that the correction factor to the pdf can still be evaluated in terms of the solution to an initial value problem for the linear system of Jacobi ordinary differential equations associated with the second variation. The second novel aspect of our analysis is that we show that the Hamiltonian form of these linear Jacobi equations still provides the appropriate correction term in the inextensible, unshearable limit that is commonly adopted in polymer physics models of, e. g. DNA. Prior analyses of the inextensible case have had to introduce nonlinear and nonlocal integral constraints to express conditions on the relative displacement of the end points. Our approximation formula for the looping pdf is of quite general applicability as, in contrast to most prior approaches, no assumption is made of either uniformity of the elastic chain, nor of a straight intrinsic shape. If the chain is uniform the Jacobi system evaluated at certain minimum energy configurations has constant coefficients. In such cases our approximate pdf can be evaluated in an entirely explicit, closed form. We illustrate our analysis with a planar example of this type and compute an approximate probability of cyclization, i.e., of forming a closed loop, from a uniform elastic chain whose intrinsic shape is an open circular arc.

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Deoxyribonucleic acid (diːˈɒksᵻˌraɪboʊnjuːˌkliːᵻk,_-ˌkleɪ-; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic in

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Dario Floreano, Daniel Marbach, Thomas Schaffter

Numerous methods have been developed for inference of gene regulatory networks from expression data, however, their strengths and weaknesses remain poorly understood. Accurate and systematic evaluation of these methods is hampered by the difficulty of constructing adequate benchmarks and the lack of tools for a differentiated analysis of network predictions on such benchmarks. Here, we present the new version (3.0) of GeneNetWeaver (GNW), an open-source tool for in silico benchmark generation and performance profiling of net-work inference methods. GNW can be launched directly from any web browser and it has an intuitive graphical user interface. Using GNW it is possible to generate biologically plausible in silico gene networks and simulated expression data, which can be used as benchmarks for network inference methods. Realistic network structures are generated by extracting modules from known biological interaction networks. These networks are then endowed with dynamics using a kinetic model of transcription and translation, where transcriptional regulation is modeled using a thermodynamic approach allowing for both independent and synergistic interactions. Finally, these models are used to produce synthetic gene expression data by simulating different biological experiments. Simulations can be done either deterministically or stochastically to model internal noise in the dynamics of the networks, and experimental noise can be added using a model of noise observed in microarrays. Another important feature of GNW is systematic evaluation of the predictions from different inference methods on in silico networks in the benchmark. For a set of network predictions from one or several inference methods, GNW automatically generates a comprehensive report in PDF format. These reports include standard metrics used to assess the accuracy of network inference methods such as precision-recall and receiver operating characteristic (ROC) curves. Furthermore, the reports include network motif analysis, where the performance of inference methods is profiled on local connectivity patterns. The network motif analysis often reveals systematic prediction errors, thereby indicating potential ways of network reconstruction improvements. We are using GNW to provide an annual network inference challenge for the DREAM project. In the past three editions, a total of 91 teams submitted about 900 network predictions to evaluate the performance of their methods on GNW-generated benchmarks.

2010In this thesis we describe a path integral formalism to evaluate approximations to the probability density function for the location and orientation of one end of a continuum polymer chain at thermodynamic equilibrium with a heat bath. We concentrate on those systems for which the associated energy density is at most quadratic in its variables. Our main motivation is to exploit continuum elastic rod models for the approximate computation of DNA looping probabilities. We first re-derive, for a polymer chain system, an expression for the second order correction term due to quadratic fluctuations about a unique minimal energy configuration. The result, originally stated for a quantum mechanical system by G. Papadopoulos (1975), relies on an elegant algebraic argument that carries over to the real-valued path integrals of interest here. The conclusion is that the appropriate expression can be evaluated in terms of the energy of the minimizer and the inverse square root of the determinant of a matrix satisfying a certain non-linear system of differential equations. We then construct a change of variables, which establishes a mapping between the solutions of the aforementioned non-linear Papadopoulos equations and a matrix satisfying an initial value problem for the classic linear system of Jacobi equations associated with the second variation of the energy functional. This conclusion is trivial if no cross-term is present in the second variation, but ceases to be so otherwise. Cross-terms are always present in the application of rod models to DNA. We therefore can conclude that the second order fluctuation correction term to the probability density function for a chain is always given by the inverse square root of the determinant of a matrix of solutions to the Jacobi equations. We believe this conclusion to be original for the real-valued case when the second-variation involves cross-terms. Similar results are known for quantum mechanical systems, and, in this context, a connection between the so called Van-Hove-Morette determinant, which involves partial derivatives of the classical action with respect to the boundary values of the configuration variable, and the Jacobi determinant have also been established. We next apply the formula described above to the specific context of rods, for which the configuration space is that of framed curves, or curves in R3 × SO(3). An immediate application of our theory is possible if the rod model encompasses bend, twist, stretch and shear. However the constrained case, where the rod is considered to be inextensible and unshearable, is more standard in polymer physics. In this last case, our results are more delicate as the Lagrangian description breaks down, and the Hamiltonian formulation must be invoked. It is known that the unconstrained local minimizers approach constrained minimizers as the coefficients in the shear and extension terms of the energy are sent to infinity. Here we observe that the Hamiltonian form of the unconstrained Jacobi system similarly has a limit, so that the fluctuation correction in the path integral can still be expressed as the square root of the determinant of a matrix solution of a set of Jacobi equations appropriate to the constrained problem. As in reality DNA or biological macromolecules are certainly at least slightly shearable and extensible, the limit of the fluctuation correction is undoubtedly physically appropriate. The above theory provides a computationally highly tractable approach to the estimation of the appropriate probability density functions. For application to sequence-dependent models of DNA the associated systems of equations has non-constant coefficients, which is of little consequence for a numerical treatment, but precludes the possibility of finding closed form expressions. On the other hand the theory also applies to simplified homogeneous models. Accordingly, we conclude by applying our approach in a completely analytic and closed-form way to the computation of the approximate probability density function for a uniform, non-isotropic, intrinsically straight and untwisted rod to form a circular loop.

In this work, we focus on the Dynamical Low Rank (DLR) approximation of PDEs equations with random parameters. This can be interpreted as a reduced basis method, where the approximate solution is expanded in separable form over a set of few deterministic basis functions at each time, with the peculiarity that both the deterministic modes and the stochastic coefficients are computed on the fly and are free to adapt in time so as best describe the structure of the random solution. Our first goal is to generalize and reformulate in a variational setting the Dynamically Orthogonal (DO) method, proposed by Sapsis and Lermusiaux (2009) for the approximation of fluid dynamic problems with random initial conditions. The DO method is reinterpreted as a Galerkin projection of the governing equations onto the tangent space along the approximate trajectory to the manifold M_S , given by the collection of all functions which can be expressed as a sum of S linearly independent deterministic modes combined with S linearly independent stochastic modes. Depending on the parametrization of the tangent space, one obtains a set of nonlinear differential equations, suitable for numerical integration, for both the coefficients and the basis functions of the approximate solution. By formalizing the DLR variational principle for parabolic PDEs with random parameters we establish a precise link with similar techniques developed in different contexts such as the Multi-Configuration Time-Dependent Hartree method in quantum dynamics and the Dynamical Low-Rank approximation in the finite dimensional setting. By the use of curvature estimates for the approximation manifold M_S , we derive a theoretical bound for the approximation error of the S-terms DO solution by the corresponding S-terms best approximation at each time instant. The bound is applicable for full rank DLR approximate solutions on the largest time interval in which the best S-terms approximation is continuously differentiable in time. Secondly, we focus on parabolic equations, especially incompressible Navier-Stokes equations, with random Dirichlet boundary conditions and we propose a DLR technique which allows for the strong imposition of such boundary conditions. We show that the DLR variational principle can be set in the constrained manifold of all S rank random fields with a prescribed value on the boundary, expressed in low-rank format, with rank M smaller than S. We characterize the tangent space to the constrained manifold by means of the Dual Dynamically Orthogonal formulation, in which the stochastic modes are kept orthonormal and the deterministic modes satisfy suitable boundary conditions, consistent with the original problem. The same formulation is also used to conveniently include the incompressibility constraint when dealing with incompressible Navier-Stokes equations with random parameters. Finally, we extend the DLR approach for the approximation of wave equations with random parameters. We propose the Symplectic DO method, according to which the governing equation is rewritten in Hamiltonian form and the approximate solution is sought in the low dimensional manifold of all complex-valued random fields with fixed rank. Recast in the real setting, the approximate solution is expanded over a set of a few dynamical symplectic deterministic modes and satisfies the symplectic projection of the Hamiltonian system into the tangent space of the approximation manifold along the trajectory.