Abstracts of Publications:

Quantifying the impact of simple DNA parameters on the cyclization J-factor for single-basepair-addition families Y. Tong and R.S. Manning Scientific Reports 8 (2018) 4882

We use Monte Carlo simulation to quantify the change in cyclization J-factor within a dramatically simplified model of DNA that involves parameters for uniform stiffnesses, intrinsic twist, and intrinsic bending (including nonplanar bending). Plots of J versus DNA length over multiple periods of helical repeat are fit to a simple functional form in order to project the behavior of J over a broad range of these model parameters. In some instances, this process allows us to find families of DNA molecules (within our model) with quite different material properties, but very similar plots of J versus length, so similar as to likely to be indistinguishable by experiments. This effect is seen both for the parameter-pair of bend angle and stiffness scaling, as well as for the parameter-trio of helical repeat, bend angle, and bend non-planarity.
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Sequence-Dependent Persistence Lengths of DNA J.S. Mitchell, J. Glowacki, A.E. Grandchamp, R.S. Manning, and J.H. Maddocks J. Chem. Theory Comput. 13 (2017) 1539-1555

A Monte Carlo code applied to the cgDNA coarse-grain rigid-base model of B-form double-stranded DNA is used to predict a sequence-averaged persistence length of l_F=53.5 nm in the sense of Flory, and of l_p = 160 bp or 53.5 nm in the sense of apparent tangent-tangent correlation decay. These estimates are slightly higher than the consensus experimental values of 150 bp or 50 nm, but we believe the agreement to be good given that the cgDNA model is itself parametrized from molecular dynamics simulations of short fragments of length 10-20 bp, with no explicit fit to persistence length. Our Monte Carlo simulations further predict that there can be substantial dependence of persistence lengths on the specific sequence S of a fragment. We propose, and confirm the numerical accuracy of, a simple factorization that separates the part of the apparent tangent-tangent correlation decay l_p(S) attributable to intrinsic shape, from a part l_d(S) attributable purely to stiffness, i.e. a sequence-dependent version of what has been called sequence-averaged dynamic persistence length l_d-bar (=58.8 nm within the cgDNA model). For ensembles of both random and lambda-phage fragments, the apparent persistence length l_p(S) has a standard deviation of 4 nm over sequence, while our dynamic persistence length l_d(S) has a standard deviation of only 1 nm. However there are notable dynamic persistence length outliers, including poly(A) (exceptionally straight and stiff), poly(TA) (tightly coiled and exceptionally soft), and phased A-tract sequence motifs (exceptionally bent and stiff). The results of our numerical simulations agree reasonably well both with molecular dynamics simulation and diverse experimental data including minicircle cyclization rates and stereo cryo-electron microscopy images.
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A catalogue of stable equilibria of planar extensible or inextensible elastic rods for all possible Dirichlet boundary conditions R.S. Manning, Journal of Elasticity 115 (2014) 105-130.

We catalogue configurations that locally minimize energy for a planar elastic rod (extensible-shearable or inextensible-unshearable) subject to arbitrary Dirichlet boundary conditions in position and orientation. Via a combination of analysis and computation, we determine several bifurcation surfaces in the 3-parameter space of boundary conditions and explore how they depend on the rod material parameters, including in the inextensible limit. For each possible boundary condition, we find all stable equilibria with sufficiently low energy that they might be competitive within a Boltzmann distribution if the rod were used to model DNA with tens or hundreds of base pairs, the length-scale relevant for DNA looping. Depending on the boundary conditions, there are as many as three such equilibria.
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Diagnostic schemes for reducing epidemic size of African viral hemorrhagic fever outbreaks I.N. Okeke, R.S. Manning, and T. Pfeiffer Journal of Infection in Developing Countries 8 (2014) 1148-1159

Introduction: Viral hemorrhagic fever (VHF) outbreaks, with high mortality rates, have often been amplified in African health institutions due to person-to-person transmission via infected body fluids. By collating and analyzing epidemiological data from documented outbreaks, we observed that diagnostic delay contributes to epidemic size for Ebola and Marburg hemorrhagic fever outbreaks.

Methodology: We used a susceptible-exposed-infectious-removed (SEIR) model and data from the 1995 outbreak in Kikwit, Democratic Republic of Congo, to simulate Ebola hemorrhagic fever epidemics. Our model allows us to describe the dynamics for hospital staff separately from that for the general population, and to implement health worker-specific interventions.

Results: The model illustrates that implementing World Health Organization/US Centers for Disease Control and Prevention guidelines of isolating patients who do not respond to antimalarial and antibacterial chemotherapy reduces total outbreak size, from a median of 236, by 90% or more. Routinely employing diagnostic testing in post-mortems of patients that died of refractory fevers reduces the median outbreak size by a further 60%. Even greater reductions in outbreak size were seen when all febrile patients were tested for endemic infections or when febrile health-care workers were tested. The effect of testing strategies was not impaired by the 1-3 day delay that would occur if testing were performed by a reference laboratory.

Conclusion: In addition to improving the quality of care for common causes of febrile infections, increased and strategic use of laboratory diagnostics for fever could reduce the chance of hospital amplification of VHFs in resource-limited African health systems.
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Thermodynamic Analysis of Self-Assembly in Coiled-Coil Biomaterials B.P. Tsang, H.S. Bretscher, B. Kokona, R.S. Manning and R. Fairman, Biochemistry 50 (2011) 8548-8558.

Coiled-coil protein structural motifs have proven amenable to the design of structurally well-defined biomaterials. Mesoscale structural properties can be fairly well predicted based on rules governing the chemical interactions between the helices that define this structural motif. We explore the role of the hydrophobic core residues on the selfassembly of a coiled-coil polymer through a mutational analysis coupled with a salting-out procedure. Because the resultant polymers remain in solution, a thermodynamic approach is applied to characterize the polymer assembly using conventional equations from polymer theory to extract nucleation and elongation parameters. The stabilities and lengths of the polymers are measured using circular dichroism spectropolarimetry, sizing methods including dynamic light scattering and analytical ultracentrifugation, and atomic force microscopy to assess mesoscale morphology. Upon mutating isoleucines at two core positions to serines, we find that polymer stability is decreased while the degree of polymerization is about the same. Differences in results from circular dichroism and dynamic light scattering experiments suggest the presence of a stable intermediate state, and a scheme is proposed for how this intermediate might relate to the monomer and polymer states.
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Ineffective perturbations of a planar elastica K.M. Peterson and R.S. Manning, Involve 2 (2009) 557-578.

The bifurcation diagram for the buckling of a planar elastica under a load lambda is made up of a "trivial" branch of unbuckled configurations for all lambda and a sequence of branches of buckled configurations that are connected to the trivial branch at pitchfork bifurcation points. We use several perturbation expansions to determine how this diagram perturbs with the addition of a small intrinsic shape in the elastica, focusing in particular on the effect near the bifurcation points. We find that for almost all intrinsic shapes epsilon f(s), the difference between the buckled solution and the trivial solution is O(epsilon^(1/3)), but for some ``ineffective'' f, this difference is O(epsilon), and we find functions u_j(s) so that f is ineffective at bifurcation point number j when < f, u_j > = 0. These ineffective perturbations have important consequences in numerical simulations, in that the perturbed bifurcation diagram has sharper corners near the former bifurcation points, and there is a higher risk of a numerical simulation inadvertently hopping between branches near these corners.
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An extended conjugate point theory with application to the stability of planar buckling of an elastic rod subject to a repulsive self-potential K.A. Hoffman and R.S. Manning, SIAM Journal on Mathematical Analysis 41 (2009) 465-494.

The theory of conjugate points in the classic calculus of variations allows, for a certain class of functionals, the characterization of a critical point as stable (i.e., a local minimum) or not. In this work, we generalize this theory to more general functionals, assuming certain generic properties of the second variation operator. The extended conjugate point theory is then applied to a two-dimensional elastic rod subject to pointwise self-repulsion. The critical points are computed by numerically solving first-order integro-differential equations using a finite difference scheme. The stability of each critical point is then computed by determining conjugate points of the second variation operator. In addition, the generalized theory requires the numerical evaluation of the crossing velocity of the zero eigenvalue of the second variation operator at each conjugate point, a feature not present in the classic case (where the crossing velocity can be shown to always be negative). Results demonstrate that the repulsive potential has a stabilizing influence on some branches of critical points.
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Conjugate Points Revisited and Neumann-Neumann Problems R.S. Manning, SIAM Review 51 (2009) 193-212.

The theory of conjugate points in the calculus of variations is reconsidered with a perspective emphasizing the connection to finite-dimensional optimization. The object of central importance is the spectrum of the second-variation operator, analogous to the eigenvalues of the Hessian matrix in finite dimensions. With a few basic properties of this spectrum, one can see the logic behind the classic result that "stability requires the lack of conjugate points". Furthermore, we show how the spectral perspective allows the easy extension of the conjugate point approach to variants of the classic problems in the literature, such as problems with Neumann-Neumann boundary conditions.
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Quantitative atomic force microscopy image analysis of unusual filaments formed by Acanthamoeba castellanii myosin II rod domain D.J. Rigotti, B. Kokona, T. Horne, E.K. Acton, C.D. Lederman, K.A. Johnson, R.S. Manning, S.A. Kane, W.F. Smith, and R. Fairman, Anal. Biochem. 346 (2005) 189.

We describe a quantitative anlysis of Acanthamoeba castellanii myosin II rod domain images collected from atomic force microscope experiments. These images reveal that the rod domain forms a novel filament structure, most likely requiring unusual head-to-tail interactions. Similar filaments are aseen also in negatively stained electron microscopy images. Truncated myosins from Acathamoeba and other model organisms have been visualized before, revealing laterally associated bipolar minifilaments. In contrast, the filament structures that we observe are dominated by axial rather than lateral polymerization. The unusually small features in this structure (1-5 nm) required the development of quantitative and statistical techniques for filament image analysis. These techniques enhance the extraction of features that hitherto have been difficult to ascertain from more qualitative imaging approaches. The heights of the filaments are observed to have a bimodal distribution consistent with the diameters of a single rod domain and a pair of close-packed rod domains. Further quantitative analysis indicates that in-plane association is limited to at most a pair of rod domains. Taken together, this implies that the filaments contain no more than four rod domains laterally associated with one another, somewhat less than seen in bipolar minifilaments. Analysis of images of the filaments decorated with an anti-FLAG antibody reveals head-to-tail association with mean distances between the antibodies of 75 +/- 15 nm. We consider a set of molecular models to help interpret possible structures of the filaments.
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Link, Twist, Energy, and the Stability of DNA Minicircles K.A. Hoffman, R.S. Manning, and J.H. Maddocks, Biopolymers , 70 (2003) 145.

We describe how the stability properties of DNA minicircles can be directly read from plots of various biologically intuitive quantities along families of equilibrium configurations. Our conclusions follow from extensions of the mathematical theory of distinguished bifurcation diagrams that are applied within the specific context of an elastic rod model of minicircles. Families of equilibria arise as a twisting angle alpha is varied. This angle is intimately related to the continuously varying linking number Lk for nicked DNA configurations that is defined as the sum of Twist and Writhe. We present several examples of such distinguished bifurcation diagrams involving plots of the energy E, linking number Lk, and a twist moment m3, along families of cyclized equilibria of both intrinsically straight, and intrinsically curved, DNA fragments.
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Stability of an elastic rod buckling into a soft wall R.S. Manning and G.B. Bulman, Proc. R. Soc. Lon. Ser. A, 461 (2005) 2423.

The conjugate point theory of the calculus of variations is extended to apply to the buckling of an elastic rod in an external field, using the operator approach presented in (Manning, Rogers, and Maddocks, Proc. Roy. Soc. A 454 (1998) 3047), which we show can be used when the second variation operator is an integrodifferential operator, rather than a differential operator as in the classical case. The external field is chosen to model two parallel "soft" walls. We consider the examples of 2D buckling under both pinned-pinned and clamped-clamped boundary conditions, as well as the 3D clamped-clamped problem, where we consider the importance of the rod cross-section shape as it ranges from circular to extreme elliptical. For each of these problems, we find that in the appropriate limit, the soft-wall solutions approach a "hard-wall" limit, and so we make conjectures about these hard-wall contact equilibria and their stability. In the 2D pinned-pinned case, this allows us to assign stability to the configurations reported in (Holmes, Domokos, Schmitt, Szebernyi, Comput. Methods Appl. Mech. Engrg. 170 (1999) 175) and reconsider the experimental results discussed therein.
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Calculation of the stability index in parameter-dependent calculus of variations problems: Buckling of a twisted elastic strut K.A. Hoffman, R.S. Manning, and R.C. Paffenroth, SIAM Journal on Applied Dynamical Systems 1 (2002) 115.

We consider the problem of minimizing the energy of an inextensible elastic strut with length 1 subject to an imposed twist angle and force. In a standard calculus of variations approach, one first locates equilibria by solving the Euler-Lagrange ODE with boundary conditions at arclength values 0 and 1. Then, one classifies each equilibrium by counting conjugate points, with local minima corresponding to equilibria with no conjugate points. These conjugate points are arclength values sigma <= 1 at which a second ODE (the Jacobi equation) has a solution vanishing at 0 and sigma.

Finding conjugate points normally involves the numerical solution of a set of initial value problems for the Jacobi equation. For problems involving a parameter lambda, such as the force or twist angle in the elastic strut, this computation must be repeated for every value of lambda of interest.

Here we present an alternative approach that takes advantage of the presence of a parameter lambda. Rather than search for conjugate points sigma <= 1 at a fixed value of lambda, we search for a set of special parameter values lambdam (with corresponding Jacobi solution zetam) for which sigma=1 is a conjugate point. We show that under appropriate assumptions, the index of an equilibrium at any lambda equals the number of these zetam for which the inner product of zetam with S zetam is negative, where S is the Jacobi differential operator at lambda. This computation is particularly simple when lambda appears linearly in S.

We apply this approach to the elastic strut, in which the the force appears linearly in S, and as a result, we locate the conjugate points for any twisted unbuckled rod configuration without resorting to numerical solution of differential equations. In addition, we numerically compute 2-dimensional sheets of buckled equilibria (as the two parameters of force and twist are varied) via a coordinated family of one-dimensional parameter continuation computations. Conjugate points for these buckled equilibria are determined by numerical solution of the Jacobi ODE.
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Stability of $n$-covered circles for elastic rods with constant planar intrinsic curvature , R.S. Manning and K.A. Hoffman, Journal of Elasticity 62 (2001) 1.

A stability index is computed for the n-covered circular equilibria of inextensible-unshearable elastic rods with constant planar intrinsic curvature u and constant values for the twisting stiffness and two bending stiffnesses. A simple expression is derived for the index as a function of u, p (the ratio of bending stiffness out of the plane of curvature to bending stiffness in the plane of curvature), and g (the ratio of twisting stiffness to bending stiffness in the plane of curvature). In particular, for intrinsically straight rods (u=0) we prove that the 1-covered circle is stable if and only if p >= 1, and the n-covered circle (n>1) is stable if and only if g>1, p>1, and (n-1)2/n2 <= (g-1)(p-1)/(gp).

The index is computed by framing the standard Euler-Cosserat equilibrium equations within a constrained variational principle with an isoperimetric constraint ensuring the ring closure. The fact that u appears linearly in the second variation allows the second variation to be diagonalized using the eigenvectors of an appropriate eigenvalue problem similar to a Sturm-Liouville problem. This diagonalization allows the direct computation of an unconstrained index (disregarding ring closure). We then apply a result of Maddocks to find the constrained index in terms of this unconstrained index and a correction computable from the linearized constraint.
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Multiple Equilibria in DNA rings, P. Furrer, R.S. Manning and J.H. Maddocks, to appear in Biophysical Journal

Within the context of DNA rings, we analyze the relationship between intrinsic shape and the existence of multiple stable equilibria, either nicked, or cyclized with the same link. A simple test, based on a perturbation expansion of symmetry-breaking within a continuum elastic rod model, provides good predictions of the occurrence of such multiple equilibria. The reliability of these predictions is verified by direct computation of nicked and cyclized equilibria for several thousand DNA minicircles with lengths of 200 and 900 basepairs. Further, our computations of equilibria for nicked rings predict properties of the equilibrium distribution of link, as calculated by much more computationally intensive Monte Carlo simulations.
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Symmetry breaking and the Twisted Elastic Ring, R.S. Manning and J.H. Maddocks, Computer Methods in Applied Mechanics and Engineering 370 (1999) 313.

Symmetry breaking is considered in the context of a parameter-dependent two-point boundary value problem describing a twisted elastic ring that arises as a model of DNA minicircles. We explicitly determine, via a perturbation expansion, those representatives of a manifold of solutions to a symmetric BVP that persist when the symmetry is broken. Conditions generating a generic splitting are identified, and some degenerate cases are studied. In both the generic and degenerate cases, the results of the perturbation expansion are used to improve the efficiency of existing algorithms for computing symmetry-broken bifurcation diagrams.
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Isoperimetric conjugate points with application to the stability of DNA minicircles, R.S. Manning, K.A. Rogers and J.H. Maddocks, Proceedings of the Royal Society of London, Series A 454 (1998) 3047.

A conjugate point test determining an index of the constrained second variation in one-dimensional isoperimetric calculus of variations problems is described. The test is then implemented numerically to determine stability properties of equilibria within a continuum mechanics model of DNA minicircles.
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Interactive computation, parameter continuation, and visualization, J.H. Maddocks, R.S. Manning, R.C. Paffenroth, K.A. Rogers, and J.A. Warner, Int. J. Bif. Chaos 7 (1997) 1699.

Nonlinear problems arising in modelling applications are frequently parameter dependent, so that families of solutions are of interest. Such problems naturally lend themselves to interactive computation that exploits parameter continuation methods combined with visualization techniques. Visualization provides both understanding of the solution set and feedback for computational steering. We describe various issues that have arisen in our investigations of problems of this general type.
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A Continuum Rod Model of Sequence-Dependent DNA Structure, R.S. Manning, J.H. Maddocks and J.D. Kahn, J. Chem. Phys. 105 (1996) 5626.

Experimentally motivated parameters from a base-pair-level discrete DNA model are averaged to yield parameters for a continuum elastic rod with a curved unstressed shape reflecting the local DNA geometry. The continuum model permits computations with discretization lengths longer than the intrinsic discretization of the base-pair model, and, for this and other reasons, yields an efficient computational formulation. Obtaining continuum stiffnesses is straightforward, but obtaining a continuum unstressed shape is hindered by the "noisy" small-scale structure and rapid helix twist of the discrete unstressed shape. Filtering of the discrete data and an analytic transformation from the true normal-vector field to a natural (untwisted) frame allows a stable continuum fit. Equilibrium energies of closed rings predicted by the continuum model are found to match the energies of the underlying discrete model to within 0.5%. The model is applied to a set of 11 short DNA molecules (approximately 150 bp) and properly distinguishes their cyclization probabilities (J factors) when compared both to experimental cyclization rates and to Monte Carlo simulations. The continuum model does not include entropic contributions to the free energy. However, because of its rapid and accurate computation of internal energy, the continuum model should, when combined with further work on entropic effects, be a useful method for computing experimental DNA free energies.
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A uniform regularized semiclassical propagator for the 1/x^2 potential, R.S. Manning and G.S. Ezra, Phys. Rev. A, 53 (1996) 661.

We apply recent methods for semiclassical time propagation involving non-Cartesian variables to the repulsive 1D potential V(x)=x-2, x >= 0. In order to properly treat non-Cartesian variables, a quantum regularization is first performed which leads to a Langer-type potential correction term in the Gutzwiller-Van Vleck propagator. A non-uniform semiclassical treatment of V(x)=x-2 using this regularization gives an improvement to earlier unregularized results, and a uniform regularized propagator is very nearly exact for all times.
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Regularized semiclassical radial propagator for the Coulomb potential, R.S. Manning and G.S. Ezra, Phys. Rev. A, 50 (1994) 954.

We derive a regularized semiclassical radial propagator for the Coulomb potential, a case for which standard approaches run into well-known difficulties associated with a non-Cartesian radial coordinate and a potential singularity. Following Kleinert [ Path Integrals in Quantum Mechanics, Statistical Mechanics and Polymer Physics (World Scientific, Singapore, 1990)], we first perform a quantum-mechanical regularization of the propagator. The semiclassical limit is then obtained by stationary phase. The semiclassical propagator so derived has the standard Van Vleck-Gutzwiller form for the radial Coulomb problem with a potential correction (Langer modification) term included. The regularized semiclassical propagator is applied to compute the autocorrelation function for a Gaussian Rydberg wavepacket.
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Theory of Projected Probabilities on Non-Orthogonal States: Application to Electron Populations in Molecules, R.S. Manning and N. De Leon, J. Math. Chem., 5 (1990) 323.

Often it is important to consider the expansion of a quantum state z in terms of physically meaningful basis states. For example, molecular orbitals can be expressed as linear combinations of atomic orbitals, or vibrational states can be expressed as superpositions of local or normal mode eigenstates. In such expansions, it then becomes desirable to determine how much "character" a quantum state has in one of these basis states. One way of accomplishing this task is to calculate the projected probability of z on basis state j. In this paper, we consider this general quantum mechanical problem. If the basis states are orthonormal, then the projected probability of z on j is of course the square of their inner product. However, if the basis states are not orthogonal, then this result is no longer valid and one must develop a more general theory to calculate these projected probabilities. An earlier paper used one-dimensional projection operators to initiate this theory and gave closed-form results for the case of two non-orthogonal basis states (DeLeon and Neshyba, Chem. Phys. Lett. 151 (1988) 296). One- and many-dimensional projection operators, together with linear algebraic techniques, are used to extend this theory to the n non-orthogonal basis state case. Explicit closed-form results are given for the two- and three-state cases, and a general algorithm is developed for the case of four or more basis states. Application of the theory is made to atomic populations in three- to six-atom molecules, and comparisons are made to the related work of Mulliken.
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Filtration of sickle cells: recruitment into a rigid fraction as a function of density and oxygen tension, E.A. Schmalzer, R.S. Manning, and S. Chien, J. Lab. Clin. Med., 113 (1989) 727.
The rheological behavior of sickle cells was evaluated with a constant flow filtration system at 37o C by using filters with pores of 4.8 micrometer diameter. Analysis of the shape of the pressure-time curves suggested that sickle cells were subdivided into two discrete subpopulations: (1) relatively deformable cells and (2) cells so rigid that they plugged the pores. The analysis allowed calculation of the fraction of cells causing plugging F, even when F represented less than 0.01% of the population. F rose with falling O2 pressure level, apparently with the recruitment of progressively less dense cells into the plugging fraction. A density profile for each sample was constructed. When we made the assumption that the plugging cells represented the denser moiety, this profile allowed identification of the threshold O2 pressure level at which cells of a given density, deoxygenated under these conditions, became unable to traverse the 4.8 micrometer pore.
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