Biomedical subjects

Patrick B Warren

Publications and source records attributed to Patrick B Warren.

9 recordsLinked to original sources

PubMed2006

Exact results for noise power spectra in linear biochemical reaction networks.

We present a simple method for determining the exact noise power spectra and related statistical properties for linear chemical reaction networks. The method is applied to reaction networks which are representative of biochemical processes such as gene expression. We find, for example, that a post-translational modification reaction can reduce the noise associated with gene expression. Our results also indicate how to coarse grain networks by the elimination of fast reactions. In this context we have discovered a breakdown of the sum rule which relates the noise power spectrum to the total noise. The breakdown can be quantified by a sum rule deficit, which is found to be universal, and can be attributed to the high-frequency noise in the fast reactions.

Gene Expression Regulation, Bacterial↗

PubMed2006

Signal detection, modularity, and the correlation between extrinsic and intrinsic noise in biochemical networks.

We present an expression for the power spectrum of the output signal of a biochemical network, which reveals that the reactions that allow a network to detect biochemical signals, induce correlations between the extrinsic noise of the input signals and the intrinsic noise of the reactions that form the network. We show that anticorrelations between the extrinsic and intrinsic noise enhance the robustness of zero-order ultrasensitive networks to biochemical noise. We discuss the consequences for a modular description of noise transmission using the mitogen-activated protein kinase cascade.

Biochemistry↗

PubMed2006

Phase separation, interface properties, and charge density waves in a simplified model for a macroion suspension.

A simplified density functional theory for a macroion suspension is examined, where the correlation free energy corresponds to the macroion self-energy, treated within a linearized or Debye-Hückel approximation. The model possesses a miscibility gap (liquid-liquid phase separation) at low ionic strength. Within the gap, density profiles, electrical structure, and surface tension are calculated for the interface between coexisting phases, using a variational approximation. Additionally, structure factors are calculated for the homogeneous system. As one approaches the critical points, the structure factors can diverge at a nonzero wave vector, signaling the onset of charge density wave phases. Although the quantitative results should be treated with care, the results may be indicative of the rich phenomenology that can arise in asymmetric charged systems.

Journal Article↗

PubMed2005

Chemical models of genetic toggle switches.

We study by mean-field analysis and stochastic simulations chemical models for genetic toggle switches formed from pairs of genes that mutually repress each other. To determine the stability of the genetic switches, we make a connection with reactive flux theory and transition state theory. The switch stability is characterized by a well-defined lifetime tau. We find that tau grows exponentially with the mean number N of transcription factor molecules involved in the switching. In the regime accessible to direct numerical simulations, the growth law is well-characterized by tau approximately N(alpha) exp(bN), where alpha and b are parameters. The switch stability is decreased by phenomena that increase the noise in gene expression, such as the production of multiple copies of a protein from a single mRNA transcript (shot noise) and fluctuations in the number of proteins produced per transcript. However, robustness against biochemical noise can be drastically enhanced by arranging the transcription factor binding domains on the DNA such that competing transcription factors mutually exclude each other on the DNA. We also elucidate the origin of the enhanced stability of the exclusive switch with respect to that of the general switch; while the kinetic prefactor is roughly the same for both switches, the "barrier" for flipping the switch is significantly higher for the exclusive switch than that for the general switch.

Animals↗

PubMed2005

Sampling rare switching events in biochemical networks.

Bistable biochemical switches are widely found in gene regulatory networks and signal transduction pathways. Their switching dynamics are difficult to study, however, because switching events are rare, and the systems are out of equilibrium. We present a simulation method for predicting the rate and mechanism of the flipping of these switches. We apply it to a genetic switch and find that it is highly efficient. The path ensembles for the forward and reverse processes do not coincide. The method is widely applicable to rare events and nonequilibrium processes.

Bacteriophage lambda↗

PubMed2004

Multiscale modelling of human hair.

We present a multiscale modelling approach to the mechanics of human hair fibres. On the microscale, a coiled coil of filament proteins was mechanically unfolded in a molecular-dynamics simulation. The force at unfolding was found to be ca. 1 nN, which we estimated to be an order of magnitude above the reversible force. Using the concept of folded/unfolded states, we developed a statistical mechanical model, which predicts a linear decrease of the yield stress with temperature. This was confirmed experimentally by stretching human hair fibres into the yield region at elevated temperatures. The role of correlation between unfolding units has been studied in more detail predicting an energy of ca. 12 kJ mol(-1) for the interface. The composite structure of hair at the nanometre scale was addressed using a particle-based model for a macrofibril. Mesoscale particles representing coiled coils of keratin proteins were assembled to filaments and embedded in a matrix of soft particles cross-linked to a network. The macrofibril was extended in a non-equilibrium computer simulation, while monitoring the tensile force. Thermal properties of the macrofibril in the yield region are in correspondence with the two-state model.

Computer Simulation↗

PubMed2004

Late stage kinetics for various wicking and spreading problems.

The kinetics of spreading of a liquid drop in a wedge or V-shaped groove, in a network of such grooves, and on a hydrophilic strip, is reexamined. The length of a droplet of volume Omega spreading in a wedge after a time t is predicted to scale as Omega(1/5) t(2/5), and the height profile is predicted to be a parabola in the distance along the wedge. If the droplet is spreading radially in a sparse network of V-shaped grooves on a surface, the radius is predicted to scale as Omega(1/6) t(1/3), provided the liquid is completely contained within the grooves. A number of other results are also obtained.

Journal Article↗

PubMed2004

Enhancement of the stability of genetic switches by overlapping upstream regulatory domains.

We study genetic switches formed from pairs of mutually repressing operons. The switch stability is characterized by a well-defined lifetime, which grows very rapidly, albeit subexponentially, with the number of copies of the most-expressed transcription factor. The switch stability can be drastically enhanced by overlapping the upstream regulatory domains such that competing regulatory molecules mutually exclude each other. Our results suggest that robustness against biochemical noise can provide a selection pressure that drives operons together in the course of evolution.

Computer Simulation↗

PubMed2003

Linking atomistic and mesoscale simulations of water-soluble polymers.

A link between molecular and mesoscopic simulations for water-soluble polymers is made using the potential of mean force (PMF) method. Mesoscale parameters are adjusted to match selected thermodynamic quantities such as the monomer second virial coefficient or the limiting slope of the monomer adsorption isotherm, which are computed directly from atomistic PMFs. The method is illustrated by computing the bulk and surface interaction parameters (chi parameters in self-consistent field theory) for the adsorption of ethylene oxide (EO) and propylene oxide (PO) polymers from aqueous solution onto silica.

Journal Article↗