31,147 research outputs found
The macroscopic effects of microscopic heterogeneity
Over the past decade, advances in super-resolution microscopy and
particle-based modeling have driven an intense interest in investigating
spatial heterogeneity at the level of single molecules in cells. Remarkably, it
is becoming clear that spatiotemporal correlations between just a few molecules
can have profound effects on the signaling behavior of the entire cell. While
such correlations are often explicitly imposed by molecular structures such as
rafts, clusters, or scaffolds, they also arise intrinsically, due strictly to
the small numbers of molecules involved, the finite speed of diffusion, and the
effects of macromolecular crowding. In this chapter we review examples of both
explicitly imposed and intrinsic correlations, focusing on the mechanisms by
which microscopic heterogeneity is amplified to macroscopic effect.Comment: 20 pages, 5 figures. To appear in Advances in Chemical Physic
Functional Bias and Spatial Organization of Genes in Mutational Hot and Cold Regions in the Human Genome
The neutral mutation rate is known to vary widely along human chromosomes,
leading to mutational hot and cold regions. We provide evidence that categories
of functionally-related genes reside preferentially in mutationally hot or cold
regions, the size of which we have measured. Genes in hot regions are biased
toward extra-cellular communication (surface receptors, cell adhesion, immune
response, etc.) while those in cold regions are biased toward essential
cellular processes (gene regulation, RNA processing, protein modification,
etc.). From a selective perspective, this organization of genes could minimize
the mutational load on genes that need to be conserved and allow fast evolution
for genes that must frequently adapt. We also analyze the effect of gene
duplication and chromosomal recombination, which contribute significantly to
these biases for certain categories of hot genes. Overall, our results show
that genes are located non-randomly with respect to hot and cold regions,
offering the possibility that selection acts at the level of gene location in
the human genome.Comment: 17 pages, 6 figures, 2 tables. accepted to PLOS Biology, Feb. 2004
issu
The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state
We introduce and analyze a minimal model of epigenetic silencing in budding
yeast, built upon known biomolecular interactions in the system. Doing so, we
identify the epigenetic marks essential for the bistability of epigenetic
states. The model explicitly incorporates two key chromatin marks, namely H4K16
acetylation and H3K79 methylation, and explores whether the presence of
multiple marks lead to a qualitatively different systems behavior. We find that
having both modifications is important for the robustness of epigenetic
silencing. Besides the silenced and transcriptionally active fate of chromatin,
our model leads to a novel state with bivalent (i.e., both active and
silencing) marks under certain perturbations (knock-out mutations, inhibition
or enhancement of enzymatic activity). The bivalent state appears under several
perturbations and is shown to result in patchy silencing. We also show that the
titration effect, owing to a limited supply of silencing proteins, can result
in counter-intuitive responses. The design principles of the silencing system
is systematically investigated and disparate experimental observations are
assessed within a single theoretical framework. Specifically, we discuss the
behavior of Sir protein recruitment, spreading and stability of silenced
regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the
controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page
Transport of quantum excitations coupled to spatially extended nonlinear many-body systems
The role of noise in the transport properties of quantum excitations is a
topic of great importance in many fields, from organic semiconductors for
technological applications to light-harvesting complexes in photosynthesis. In
this paper we study a semi-classical model where a tight-binding Hamiltonian is
fully coupled to an underlying spatially extended nonlinear chain of atoms. We
show that the transport properties of a quantum excitation are subtly modulated
by (i) the specific type (local vs non-local) of exciton-phonon coupling and by
(ii) nonlinear effects of the underlying lattice. We report a non-monotonic
dependence of the exciton diffusion coefficient on temperature, in agreement
with earlier predictions, as a direct consequence of the lattice-induced
fluctuations in the hopping rates due to long-wavelength vibrational modes. A
standard measure of transport efficiency confirms that both nonlinearity in the
underlying lattice and off-diagonal exciton-phonon coupling promote transport
efficiency at high temperatures, preventing the Zeno-like quench observed in
other models lacking an explicit noise-providing dynamical system
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Evolutionary Covariant Positions within Calmodulin EF-hand Sequences Promote Ligand Binding
Intracellular calcium signaling is an essential regulatory mechanism through calcium-mediated signal transduction pathways involved in many cell processes, such as exocytosis, motility, apoptosis, excitability, transcription, and muscle contraction. The calcium-binding, ubiquitous, and highly conserved protein calmodulin (CaM) is an important regulator of hundreds of target proteins involved in cellular calcium signaling. CaM comprises of two pairs of EF-hand calcium-binding domains and these structural regions of the protein are highly conserved. Studying the molecular mechanisms underlying the binding of calcium to the EF-hands of CaM is critical in understanding the calcium-mediated cellular processes and how improper binding of calcium can lead to various human pathologies. Previous site-specific binding measurements indicate that each of the four EF-hands of CaM have distinct affinities for calcium. In this study, we have utilized covariance patterns and site-specific mutagenesis to analyze calcium affinity in the two EF-hands of the N-lobe of CaM in order to determine the specific amino acids that are evolutionarily conserved to coordinate calcium. The specific amino acids in CaM that we studied are theorized to coevolve, which means that in their protein coding genes, when a mutation occurs, a compensatory mutation is likely to follow to conserve structure and function of CaM. Since CaM is a highly conserved protein with a known structure, covariance analyses will help in understanding which amino acid contacts are most important for the coordination of calcium in the EF-hands of CaM and to determine which amino acids are under evolutionary constraint. Covariance algorithms, multiple sequence analyses and accompanied protein structure analyses were used to identify the two high scoring amino acid pairs in the N-lobe EF-hands: positions 22 and 24 in EF-hand site 1 and positions 58 and 60 in EF-hand site 2. The amino acids in these locations were mutated and accompanied calcium binding was measured to better understand the effects of the mutations on calcium binding. We have found that both the D24N mutation in site 1 and the D58N mutation in site 2 disrupt binding likely due to the removal of a necessary aspartate in the binding site. However, the combined D58N and N60D mutations restore binding in site 2 by providing the necessary aspartate in the covariant location. The N60D mutation by itself has little impact on calcium binding in site 2. Therefore, it is evident that evolution conserves at least one aspartate in the covariant positions of the binding site and the presence of two aspartates in the covariant positions of the binding site has little affect on calcium binding. We are currently studying the covariant positions in site 1 and future work includes structurally analyzing the covariant positions in the C-lobe of CaM and studying covariance patterns of other calcium-binding proteins with EF-hand binding domains.Biochemistr
Fundamental Limits to Position Determination by Concentration Gradients
Position determination in biological systems is often achieved through
protein concentration gradients. Measuring the local concentration of such a
protein with a spatially-varying distribution allows the measurement of
position within the system. In order for these systems to work effectively,
position determination must be robust to noise. Here, we calculate fundamental
limits to the precision of position determination by concentration gradients
due to unavoidable biochemical noise perturbing the gradients. We focus on
gradient proteins with first order reaction kinetics. Systems of this type have
been experimentally characterised in both developmental and cell biology
settings. For a single gradient we show that, through time-averaging, great
precision can potentially be achieved even with very low protein copy numbers.
As a second example, we investigate the ability of a system with oppositely
directed gradients to find its centre. With this mechanism, positional
precision close to the centre improves more slowly with increasing averaging
time, and so longer averaging times or higher copy numbers are required for
high precision. For both single and double gradients, we demonstrate the
existence of optimal length scales for the gradients, where precision is
maximized, as well as analyzing how precision depends on the size of the
concentration measuring apparatus. Our results provide fundamental constraints
on the positional precision supplied by concentration gradients in various
contexts, including both in developmental biology and also within a single
cell.Comment: 24 pages, 2 figure
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