Space in systems biology of signaling pathways – towards intracellular molecular crowding in silico

Takahashi, Kyôko; Arjunan, Satya N.V.; Tomita, Masaru

doi:10.1016/j.febslet.2005.01.072

Cited by 208 publications

(178 citation statements)

References 52 publications

(70 reference statements)

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…Particle-based methods such as Brownian dynamics (BD) and molecular dynamics simulations have traditionally been used to explore such interactions in crowded cellular environments (reviewed in Ref. 5), but typically at a computational expense that is ora) Electronic mail: pkekeneshuskey@ucsd.edu ders of magnitude greater than continuum approaches, which limits their application to small systems.…”

Section: Introductionmentioning

confidence: 99%

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Kekenes‐Huskey

Gillette

McCammon

2014

The Journal of Chemical Physics

View full text Add to dashboard Cite

The macroscopic diffusion constant for a charged diffuser is in part dependent on (1) the volume excluded by solute "obstacles" and (2) long-range interactions between those obstacles and the diffuser. Increasing excluded volume reduces transport of the diffuser, while long-range interactions can either increase or decrease diffusivity, depending on the nature of the potential. We previously demonstrated [P. M. Kekenes-Huskey et al., Biophys. J. 105, 2130] using homogenization theory that the configuration of molecular-scale obstacles can both hinder diffusion and induce diffusional anisotropy for small ions. As the density of molecular obstacles increases, van der Waals (vdW) and electrostatic interactions between obstacle and a diffuser become significant and can strongly influence the latter's diffusivity, which was neglected in our original model. Here, we extend this methodology to include a fixed (time-independent) potential of mean force, through homogenization of the Smoluchowski equation. We consider the diffusion of ions in crowded, hydrophilic environments at physiological ionic strengths and find that electrostatic and vdW interactions can enhance or depress effective diffusion rates for attractive or repulsive forces, respectively. Additionally, we show that the observed diffusion rate may be reduced independent of non-specific electrostatic and vdW interactions by treating obstacles that exhibit specific binding interactions as "buffers" that absorb free diffusers. Finally, we demonstrate that effective diffusion rates are sensitive to distribution of surface charge on a globular protein, Troponin C, suggesting that the use of molecular structures with atomistic-scale resolution can account for electrostatic influences on substrate transport. This approach offers new insight into the influence of molecular-scale, long-range interactions on transport of charged species, particularly for diffusion-influenced signaling events occurring in crowded cellular environments.

show abstract

Section: Introductionmentioning

confidence: 99%

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Kekenes‐Huskey

Gillette

McCammon

2014

The Journal of Chemical Physics

View full text Add to dashboard Cite

show abstract

“…Finally, using high-throughput microfluidics, visualization of molecular movement within whole cells allows for the large-scale determination of dynamic properties, including temporal and spatial characterizations, a dimension only recently gaining popular consideration in the development of mathematical models of biological systems. [14][15][16] Currently, the biggest roadblock in the large-scale application of microfluidic engineering to systems biology is the lack of experimental compatibility with established methodologies. While the current focus of the field is in validating the fundamental advantages of microfabricated systems, the next stage of development needs to address the engineering of functional instrumentation to exploit the novel advantages noted above.…”

Section: Professor Luke P Lee Is L L O Y D D I S T I N G U I S H E Dmentioning

confidence: 99%

“…The experiment took into account the spatial context of cellular signaling and only recently has spatial heterogeneity been seriously gaining momentum as a necessary dimension to consider in systems biology modeling and simulation. 12,[14][15][16] On a cellular systems scale, Lucchetta et al 27 used localized microfluidic flow to explore embryonic patterning compensation mechanisms against spatiotemporal perturbations applied to a Drosophila embryo. The robustness of the Drosophila patterning system to a large range of physicochemical parameters has been well-demonstrated using system-level mathematical models.…”

Section: Exploiting Microfluidic Flow For Unique Opportunities In Expmentioning

confidence: 99%

Microfluidics-based systems biology

2006

View full text Add to dashboard Cite

Systems biology seeks to develop a complete understanding of cellular mechanisms by studying the functions of intra-and inter-cellular molecular interactions that trigger and coordinate cellular events. However, the complexity of biological systems causes accurate and precise systems biology experimentation to be a difficult task. Most biological experimentation focuses on highly detailed investigation of a single signaling mechanism, which lacks the throughput necessary to reconstruct the entirety of the biological system, while high-throughput testing often lacks the fidelity and detail necessary to fully comprehend the mechanisms of signal propagation. Systems biology experimentation, however, can benefit greatly from the progress in the development of microfluidic devices. Microfluidics provides the opportunity to study cells effectively on both a single-and multi-cellular level with high-resolution and localized application of experimental conditions with biomimetic physiological conditions. Additionally, the ability to massively array devices on a chip opens the door for high-throughput, high fidelity experimentation to aid in accurate and precise unraveling of the intertwined signaling systems that compose the inner workings of the cell.

show abstract

“…Therefore, realistic simulations require modeling of active transport processes, that can be measured experimentally (7). Molecular crowdings may play an important role, but need to be considered as unequally distributed in cellular compartments (8). Many cellular activities are based on localized protein concentrations and the concert of distinct activity patterns in cellular organelles (9), culminating in specific phenotypical responses.…”

Section: Space In Systems Biologymentioning

confidence: 99%

Cytomics in the realm of systems biology

Kriete

2005

Cytometry Pt A

View full text Add to dashboard Cite

CONVERGENCE OF SYSTEMS BIOLOGYAND CYTOMICS The current focus of systems biology is on the reverse engineering of networks to model gene regulatory or protein-protein interactions and the extraction of basic principles of biological organization. The ability of in silico representations to predict of how a system being in a particular state may react and adjust to perturbations has made systems biology an attractive component for basic research, drug development, and predictive medicine. However, computational systems biology is less experienced in implementing spatiotemporal properties of cells and multicellular architectures, and attempts to integrate and interconnect various levels of biological organization, such as genes, proteins, cells, and tissues, are a rare occurrence.As opinions about the nature of Cytomics as a discipline arise, and activities and projects evolve, more specific definitions may become available. At this point it should be noted that even systems biology, which already has a track record of successful research activities, still experiences debates of what it is or should be. Cytomics is currently centered on high-throughput, multiparametric imaging in conjunction with machine vision to quantify cellular morphologies and properties like protein activities, with the underlying notion of a hypothesis-free approach. It aims to provide comprehensive, accurate, unbiased and systematic data, features that have been defined as the cornerstones for measurement technologies in systems biology (1). Applications for a systematic profiling of different cells, such as all cell types in the human body, have been suggested (2). Systematic screening projects will enable us to populate a rather sparse data area above the level of the proteome.Cytomics appreciates single cell properties, which is of great value since averaging can seriously limit systems biology approaches, such as network analyses. The example recently demonstrated applied reverse engineering in T-cells, using multiparameter flow cytometry and Baysian statistics (3). Targeting multiple protein activators and inhibitors allowed simultaneous monitoring of the phosphorylation status of many protein species. As each pathway in each cell is in a particular status of activation, signaling networks can be more accurately revealed by taking multiparameter snapshots of many cells when compared to procedures that rely on averaged information out of cell lysates. SPACE IN SYSTEMS BIOLOGYCytomics introduces something new that systems biology has not thoroughly considered yet: The ability to image makes quantitative spatial (and time resolved) measures of protein distributions and local concentrations, patterns related to organelles, and properties of transport phenomena between intracellular compartments available. Related projects include single cell-based response evaluation to drug treatment (4), pattern recognition of localized protein distributions that improve currently available ontologies (5), as well as analysis of changes of subcellular ph...

show abstract

Space in systems biology of signaling pathways – towards intracellular molecular crowding in silico

Cited by 208 publications

References 52 publications

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

Microfluidics-based systems biology

Cytomics in the realm of systems biology

Contact Info

Product

Resources

About