2,138 research outputs found
Stepwise Acquisition of Pyrimethamine Resistance in the Malaria Parasite
The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.Organismic and Evolutionary Biolog
Impact of observational incompleteness on the structural properties of protein interaction networks
The observed structure of protein interaction networks is corrupted by many
false positive/negative links. This observational incompleteness is abstracted
as random link removal and a specific, experimentally motivated (spoke) link
rearrangement. Their impact on the structural properties of
gene-duplication-and-mutation network models is studied. For the degree
distribution a curve collapse is found, showing no sensitive dependence on the
link removal/rearrangement strengths and disallowing a quantitative extraction
of model parameters. The spoke link rearrangement process moves other
structural observables, like degree correlations, cluster coefficient and motif
frequencies, closer to their counterparts extracted from the yeast data. This
underlines the importance to take a precise modeling of the observational
incompleteness into account when network structure models are to be
quantitatively compared to data.Comment: 17 pages, 7 figures, accepted by Physica
Non-equilibrium phase transitions in biomolecular signal transduction
We study a mechanism for reliable switching in biomolecular
signal-transduction cascades. Steady bistable states are created by system-size
cooperative effects in populations of proteins, in spite of the fact that the
phosphorylation-state transitions of any molecule, by means of which the switch
is implemented, are highly stochastic. The emergence of switching is a
nonequilibrium phase transition in an energetically driven, dissipative system
described by a master equation. We use operator and functional integral methods
from reaction-diffusion theory to solve for the phase structure, noise
spectrum, and escape trajectories and first-passage times of a class of minimal
models of switches, showing how all critical properties for switch behavior can
be computed within a unified framework
DMAPS: a database of multiple alignments for protein structures
The database of multiple alignments for protein structures (DMAPS) provides instant access to pre-computed multiple structure alignments for all protein structure families in the Protein Data Bank (PDB). Protein structure families have been obtained from four distinct classification methods including SCOP, CATH, ENZYME and CE, and multiple structure alignments have been built for all families containing at least three members, using CE-MC software. Currently, multiple structure alignments are available for 3050 SCOP-, 3087 CATH-, 664 ENZYME- and 1707 CE-based families. A web-based query system has been developed to retrieve multiple alignments for these families using the PDB chain ID of any member of a family. Multiple alignments can be viewed or downloaded in six different formats, including JOY/html, TEXT, FASTA, PDB (superimposed coordinates), JOY/postscript and JOY/rtf. DMAPS is accessible online at
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Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.
RNA Polymerase II (Pol II) and transcription factors form concentrated hubs in cells via multivalent protein-protein interactions, often mediated by proteins with intrinsically disordered regions. During Herpes Simplex Virus infection, viral replication compartments (RCs) efficiently enrich host Pol II into membraneless domains, reminiscent of liquid-liquid phase separation. Despite sharing several properties with phase-separated condensates, we show that RCs operate via a distinct mechanism wherein unrestricted nonspecific protein-DNA interactions efficiently outcompete host chromatin, profoundly influencing the way DNA-binding proteins explore RCs. We find that the viral genome remains largely nucleosome-free, and this increase in accessibility allows Pol II and other DNA-binding proteins to repeatedly visit nearby DNA binding sites. This anisotropic behavior creates local accumulations of protein factors despite their unrestricted diffusion across RC boundaries. Our results reveal underappreciated consequences of nonspecific DNA binding in shaping gene activity, and suggest additional roles for chromatin in modulating nuclear function and organization
Transition probabilities for general birth-death processes with applications in ecology, genetics, and evolution
A birth-death process is a continuous-time Markov chain that counts the
number of particles in a system over time. In the general process with
current particles, a new particle is born with instantaneous rate
and a particle dies with instantaneous rate . Currently no robust and
efficient method exists to evaluate the finite-time transition probabilities in
a general birth-death process with arbitrary birth and death rates. In this
paper, we first revisit the theory of continued fractions to obtain expressions
for the Laplace transforms of these transition probabilities and make explicit
an important derivation connecting transition probabilities and continued
fractions. We then develop an efficient algorithm for computing these
probabilities that analyzes the error associated with approximations in the
method. We demonstrate that this error-controlled method agrees with known
solutions and outperforms previous approaches to computing these probabilities.
Finally, we apply our novel method to several important problems in ecology,
evolution, and genetics
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