Noise control in gene regulatory networks with negative feedback

Genes and proteins regulate cellular functions through complex circuits of biochemical reactions. Fluctuations in the components of these regulatory networks result in noise that invariably corrupts the signal, possibly compromising function. Here, we create a practical formalism based on ideas introduced by Wiener and Kolmogorov (WK) for filtering noise in engineered communications systems to quantitatively assess the extent to which noise can be controlled in biological processes involving negative feedback. Application of the theory, which reproduces the previously proven scaling of the lower bound for noise suppression in terms of the number of signaling events, shows that a tetracycline repressor-based negative-regulatory gene circuit behaves as a WK filter. For the class of Hill-like nonlinear regulatory functions, this type of filter provides the optimal reduction in noise. Our theoretical approach can be readily combined with experimental measurements of response functions in a wide variety of genetic circuits, to elucidate the general principles by which biological networks minimize noise.Comment: 20 pages, 7 figure

Anisotropic Hydrodynamic Mean-Field Theory for Semiflexible Polymers under Tension

We introduce an anisotropic mean-field approach for the dynamics of semiflexible polymers under intermediate tension, the force range where a chain is partially extended but not in the asymptotic regime of a nearly straight contour. The theory is designed to exactly reproduce the lowest order equilibrium averages of a stretched polymer, and treats the full complexity of the problem: the resulting dynamics include the coupled effects of long-range hydrodynamic interactions, backbone stiffness, and large-scale polymer contour fluctuations. Validated by Brownian hydrodynamics simulations and comparison to optical tweezer measurements on stretched DNA, the theory is highly accurate in the intermediate tension regime over a broad dynamical range, without the need for additional dynamic fitting parameters.Comment: 22 pages, 9 figures; revised version with additional calculations and experimental comparison; accepted for publication in Macromolecule

Directly measuring single molecule heterogeneity using force spectroscopy

One of the most intriguing results of single molecule experiments on proteins and nucleic acids is the discovery of functional heterogeneity: the observation that complex cellular machines exhibit multiple, biologically active conformations. The structural differences between these conformations may be subtle, but each distinct state can be remarkably long-lived, with random interconversions between states occurring only at macroscopic timescales, fractions of a second or longer. Though we now have proof of functional heterogeneity in a handful of systems---enzymes, motors, adhesion complexes---identifying and measuring it remains a formidable challenge. Here we show that evidence of this phenomenon is more widespread than previously known, encoded in data collected from some of the most well-established single molecule techniques: AFM or optical tweezer pulling experiments. We present a theoretical procedure for analyzing distributions of rupture/unfolding forces recorded at different pulling speeds. This results in a single parameter, quantifying the degree of heterogeneity, and also leads to bounds on the equilibration and conformational interconversion timescales. Surveying ten published datasets, we find heterogeneity in five of them, all with interconversion rates slower than 10 s$^{-1}$. Moreover, we identify two systems where additional data at realizable pulling velocities is likely to find a theoretically predicted, but so far unobserved cross-over regime between heterogeneous and non-heterogeneous behavior. The significance of this regime is that it will allow far more precise estimates of the slow conformational switching times, one of the least understood aspects of functional heterogeneity.Comment: Main text: 13 pages, 6 figures; SI: 9 pages, 6 figure

Global cross-over dynamics of single semiflexible polymers

We present a mean-field dynamical theory for single semiflexible polymers which can precisely capture, without fitting parameters, recent fluorescence correlation spectroscopy results on single monomer kinetics of DNA strands in solution. Our approach works globally, covering three decades of strand length and five decades of time: it includes the complex cross-overs occurring between stiffness-dominated and flexible bending modes, along with larger-scale rotational and center-of-mass motion. The accuracy of the theory stems in part from long-range hydrodynamic coupling between the monomers, which makes a mean-field description more realistic. Its validity extends even to short, stiff fragments, where we also test the theory through Brownian hydrodynamics simulations.Comment: 6 pages, 5 figures; updated with minor changes to reflect published versio

Frustrated Further-Neighbor Antiferromagnetic and Electron-Hopping Interactions in the d=3 tJ Model: Finite-Temperature Global Phase Diagrams from Renormalization-Group Theory

The renormalization-group theory of the d=3 tJ model is extended to further-neighbor antiferromagnetic or electron-hopping interactions, including the ranges of frustration. The global phase diagram of each model is calculated for the entire ranges of temperatures, electron densities, and further/first-neighbor interaction strength ratios. In addition to the \tau_{tJ} phase seen in earlier studies of the nearest-neighbor d=3 tJ model, the \tau_{Hb} phase seen before in the d=3 Hubbard model appears both near and away from half-filling. These distinct \tau phases potentially correspond to different (BEC-like and BCS-like) superconducting phases.Comment: Improved figures, added discussions, added references. Published version. 12 pages, 5 figures, 6 table

Plasticity of hydrogen bond networks regulates mechanochemistry of cell adhesion complexes

Mechanical forces acting on cell adhesion receptor proteins regulate a range of cellular functions by formation and rupture of non-covalent interactions with ligands. Typically, force decreases the lifetimes of intact complexes (slip-bonds), making the discovery that these lifetimes can also be prolonged ("catch-bonds"), a surprise. We created a microscopic analytic theory by incorporating the structures of selectin and integrin receptors into a conceptual framework based on the theory of stochastic equations, which quantitatively explains a wide range of experimental data (including catch-bonds at low forces and slip-bonds at high forces). Catch-bonds arise due to force-induced remodeling of hydrogen bond networks, a finding that also accounts for unbinding in structurally unrelated integrin-fibronectin and actomyosin complexes. For the selectin family, remodeling of hydrogen bond networks drives an allosteric transition resulting in the formation of maximum number of hydrogen bonds determined only by the structure of the receptor and is independent of the ligand. A similar transition allows us to predict the increase in number of hydrogen bonds in a particular allosteric state of $\alpha_5 \beta_1$ integrin-fibronectin complex, a conformation which is yet to be crystallized. We also make a testable prediction that a single point mutation (Tyr51Phe) in the ligand associated with selectin should dramatically alter the nature of the catch-bond compared to the wild type. Our work suggests that nature utilizes a ductile network of hydrogen bonds to engineer function over a broad range of forces.Comment: main text: 8 pages, 4 figures; SI: 5 pages, 2 figures, Proc. Natl. Acad. Sci., published online before print (2014