Artificial Epigenetic Networks: Automatic Decomposition of Dynamical Control Tasks Using Topological Self-Modification.

This paper describes the artificial epigenetic network, a recurrent connectionist architecture that is able to dynamically modify its topology in order to automatically decompose and solve dynamical problems. The approach is motivated by the behavior of gene regulatory networks, particularly the epigenetic process of chromatin remodeling that leads to topological change and which underlies the differentiation of cells within complex biological organisms. We expected this approach to be useful in situations where there is a need to switch between different dynamical behaviors, and do so in a sensitive and robust manner in the absence of a priori information about problem structure.

Recognition Dynamics of p53 and MDM2: Implications for Peptide Design.

Peptides that inhibit MDM2 and attenuate MDM2-p53 interactions, thus activating p53, are currently being pursued as anticancer drug leads for tumors harboring wild type p53. The thermodynamic determinants of peptide-MDM2 interactions have been extensively studied. However, a detailed understanding of the dynamics that underlie these interactions is largely missing.

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2.

The interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20).

Conserved two-step regulatory mechanism of human epithelial differentiation.

Human epithelia are organized in a hierarchical structure, where stem cells generate terminally differentiated cells via intermediate progenitors. This two-step differentiation process is conserved in all tissues, but it is not known whether a common gene set contributes to its regulation. Here, we show that retinoic acid (RA) regulates early human prostate epithelial differentiation by activating a tightly coexpressed set of 80 genes (e.

On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein.

The stereoselective affinity of small-molecule binding to proteins is typically broadly explained in terms of the thermodynamics of the final bound complex. Using Brownian dynamics simulations, we show that the preferential binding of the MDM2 protein to the geometrical isomers of Nutlin-3, an effective anticancer lead that works by inhibiting the interaction between the proteins p53 and MDM2, can be explained by kinetic arguments related to the formation of the MDM2:Nutlin-3 encounter complex. This is a diffusively bound state that forms prior to the final bound complex.

Computational models of signalling networks for non-linear control.

Artificial signalling networks (ASNs) are a computational approach inspired by the signalling processes inside cells that decode outside environmental information. Using evolutionary algorithms to induce complex behaviours, we show how chaotic dynamics in a conservative dynamical system can be controlled. Such dynamics are of particular interest as they mimic the inherent complexity of non-linear physical systems in the real world.

The incorporation of epigenetics in artificial gene regulatory networks.

Artificial gene regulatory networks are computational models that draw inspiration from biological networks of gene regulation. Since their inception they have been used to infer knowledge about gene regulation and as methods of computation. These computational models have been shown to possess properties typically found in the biological world, such as robustness and self organisation.

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: a Brownian dynamics study.

The interaction of p53 with its regulators MDM2 and MDMX plays a major role in regulating the cell cycle. Inhibition of this interaction has become an important therapeutic strategy in oncology. Although MDM2 and MDMX share a very high degree of sequence/structural similarity, the small-molecule inhibitor nutlin appears to be an efficient inhibitor only of the p53-MDM2 interaction.

Peptide inhibitors of viral assembly: a novel route to broad-spectrum antivirals.

We investigated the potential of small peptide segments to function as broad-spectrum antiviral drug leads. We extracted the α-helical peptide segments that share common secondary-structure environments in the capsid protein-protein interfaces of three unrelated virus classes (PRD1-like, HK97-like, and BTV-like) that encompass different levels of pathogenicity to humans, animals, and plants. The potential for the binding of these peptides to the individual capsid proteins was then investigated using blind docking simulations.

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development.

The study of drug-receptor interactions has largely been framed in terms of the equilibrium thermodynamic binding affinity, an in vitro measure of the stability of the drug-receptor complex that is commonly used as a proxy measure of in vivo biological activity. In response to the growing realization of the importance of binding kinetics to in vivo drug activity we present a computational methodology for the kinetic characterization of drug-receptor interactions in terms of the encounter complex. Using trajectory data from multiple Brownian dynamics simulations of ligand diffusion, we derive the spatial density of the ligand around the receptor and show how it can be quantitatively partitioned into different basins of attraction.

On the origin of order in the genome organization of ssRNA viruses.

Single-stranded RNA (ssRNA) viruses form a major class that includes important human, animal, and plant pathogens. While the principles underlying the structures of their protein capsids are generally well understood, much less is known about the organization of their encapsulated genomic RNAs. Cryo-electron microscopy and x-ray crystallography have revealed striking evidence of order in the packaged genomes of a number of ssRNA viruses.

The impact of viral RNA on the association rates of capsid protein assembly: bacteriophage MS2 as a case study.

A large number of single-stranded RNA viruses, which form a major class of all viruses, co-assemble their protein container and their genomic material. The multiple roles of the viral genome in this process are presently only partly understood. Recent experimental results indicate that RNA, in addition to its function as a repository for genetic information, could play important functional roles during the assembly of the viral protein containers.

Multivariate analysis of conserved sequence-structure relationships in kinesins: coupling of the active site and a tubulin-binding sub-domain.

An extensive computational analysis of available sequence and crystal structure data was used to identify functionally important residue interactions within the motor domain of the kinesin molecular motor. Principal component analysis revealed that all current kinesin crystal structures reside in one of two main conformations, which differ at the active site, and in the position of a microtubule-binding sub-domain relative to a rigid central core. This sub-domain consists of secondary structure elements alpha4-loop12-alpha5-loop13 and contains a conserved hydrophilic surface patch that may be involved in strong binding to microtubules.

Bio3d: an R package for the comparative analysis of protein structures.

Unlabelled: An automated procedure for the analysis of homologous protein structures has been developed. The method facilitates the characterization of internal conformational differences and inter-conformer relationships and provides a framework for the analysis of protein structural evolution. The method is implemented in bio3d, an R package for the exploratory analysis of structure and sequence data.

The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA.

A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers.

Mutation in myosin heavy chain 6 causes atrial septal defect.

Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain.

Molecular evolutionary convergence of the flight muscle protein arthrin in Diptera and hemiptera.

Uniquely, the asynchronous flight muscle myofibrils of many insects contain arthrin, a stable 1:1 conjugate between actin and ubiquitin. The function of arthrin is still unknown. Here we survey for the presence of arthrin in 63 species of insect across nine orders using Western blotting.

Congruent qualitative behavior of complete and reconstructed phase space trajectories from biomolecular dynamics simulation.

Central to the study of a complex dynamical system is knowledge of its phase space behavior. Experimentally, it is rarely possible to record a system's (multidimensional) phase space variables. Rather, the system is observed via one (or few) scalar-valued signal(s) of emission or response.