218 research outputs found
Conformational catalysis of cataract-associated aggregation by interacting intermediates in a human eye lens crystallin
Most known proteins in nature consist of multiple domains. Interactions
between domains may lead to unexpected folding and misfolding phenomena. This
study of human {\gamma}D-crystallin, a two-domain protein in the eye lens,
revealed one such surprise: conformational catalysis of misfolding via
intermolecular domain interface ''stealing''. An intermolecular interface
between the more stable domains outcompetes the native intramolecular domain
interface. Loss of the native interface in turn promotes misfolding and
subsequent aggregation, especially in cataract-related {\gamma}D-crystallin
variants. This phenomenon is likely a contributing factor in the development of
cataract disease, the leading worldwide cause of blindness. However, interface
stealing likely occurs in many proteins composed of two or more interacting
domains.Comment: 26 pages, 6 figures+Supplementar
Lethal Mutagenesis in Viruses and Bacteria
Here we study how mutations which change physical properties of cell proteins
(stability) impact population survival and growth. In our model the genotype is
presented as a set of N numbers, folding free energies of cells N proteins.
Mutations occur upon replications so that stabilities of some proteins in
daughter cells differ from those in parent cell by random amounts drawn from
experimental distribution of mutational effects on protein stability. The
genotype-phenotype relationship posits that unstable proteins confer lethal
phenotype to a cell and in addition the cells fitness (duplication rate) is
proportional to the concentration of its folded proteins. Simulations reveal
that lethal mutagenesis occurs at mutation rates close to 7 mutations per
genome per replications for RNA viruses and about half of that for DNA based
organisms, in accord with earlier predictions from analytical theory and
experiment. This number appears somewhat dependent on the number of genes in
the organisms and natural death rate. Further, our model reproduces the
distribution of stabilities of natural proteins in excellent agreement with
experiment. Our model predicts that species with high mutation rates, tend to
have less stable proteins compared to species with low mutation rate
Growth tradeoffs produce complex microbial communities on a single limiting resource
The relationship between the dynamics of a community and its constituent
pairwise interactions is a fundamental problem in ecology. Higher-order
ecological effects beyond pairwise interactions may be key to complex
ecosystems, but mechanisms to produce these effects remain poorly understood.
Here we show that higher-order effects can arise from variation in multiple
microbial growth traits, such as lag times and growth rates, on a single
limiting resource with no other interactions. These effects produce a range of
ecological phenomena: an unlimited number of strains can exhibit multistability
and neutral coexistence, potentially with a single keystone strain; strains
that coexist in pairs do not coexist all together; and the champion of all
pairwise competitions may not dominate in a mixed community. Since variation in
multiple growth traits is ubiquitous in microbial populations due to pleiotropy
and non-genetic variation, our results indicate these higher-order effects may
also be widespread, especially in laboratory ecology and evolution experiments
Emergence of the protein universe in organismal evolution
In this work we propose a physical model of organismal evolution, where
phenotype, organism life expectancy, is directly related to genotype i.e. the
stability of its proteins which can be determined exactly in the model.
Simulating the model on a computer, we consistently observe the Big Bang
scenario whereby exponential population growth ensues as favorable
sequence-structure combinations (precursors of stable proteins) are discovered.
After that, random diversity of the structural space abruptly collapses into a
small set of preferred structural motifs. We observe that protein folds remain
stable and abundant in the population at time scales much greater than mutation
or organism lifetime, and the distribution of the lifetimes of dominant folds
in a population approximately follows a power law. The separation of
evolutionary time scales between discovery of new folds and generation of new
sequences gives rise to emergence of protein families and superfamilies whose
sizes are power-law distributed, closely matching the same distributions for
real proteins. The network of structural similarities of the universe of
evolved proteins has the same scale-free like character as the actual protein
domain universe graph (PDUG). Further, the model predicts that ancient protein
domains represent a highly connected and clustered subset of all protein
domains, in complete agreement with reality. Together, these results provide a
microscopic first principles picture of how protein structures and gene
families evolved in the course of evolution.Comment: Replaced with revised version; power-law distributions are shown here
to emerge from microscopic model evolutionary dynamic
Thermal Adaptation in Viruses and Bacteria
A previously established multiscale population genetics model states that
fitness can be inferred from the physical properties of proteins under the
physiological assumption that a loss of stability by any protein confers the
lethal phenotype to an organism. Here we develop this model further by positing
that replication rate (fitness) of a bacterial or viral strain directly depends
on the copy number of folded proteins which determine its replication rate.
Using this model, and both numerical and analytical approaches, we studied the
adaptation process of bacteria and viruses at varied environmental
temperatures. We found that a broad distribution of protein stabilities
observed in the model and in experiment is the key determinant of thermal
response for viruses and bacteria. Our results explain most of the earlier
experimental observations: striking asymmetry of thermal response curves, the
absence of evolutionary trade-off which was expected but not found in
experiments, correlation between denaturation temperature for several protein
families and the Optimal Growth Temperature (OGT) of their host organisms, and
proximity of bacterial or viral OGTs to their evolutionary temperatures. Our
theory quantitatively and with high accuracy described thermal response curves
for 35 bacterial species using, for each species, only two adjustable
parameters, the number of replication rate determining genes and energy barrier
for metabolic reactions
Mode-coupling theory for heteropolymers
We study the Langevin dynamics of a heteropolymer by means of a mode-coupling
approximation scheme, giving rise to a set of coupled integro-differential
equations relating the response and correlation functions. The analysis shows
that there is a regime at low temperature characterized by out-of-equilibrium
dynamics, with violation of time-translational invariance and of the
fluctuation-dissipation theorem. The onset of ageing dynamics at low
temperatures gives new insight into the nature of the slow dynamics of a
disordered polymer. We also introduce a renormalization-group treatment of our
mode-coupling equations, which supports our analysis, and might be applicable
to other systems.Comment: 23 page
Mutation rate variability as a driving force in adaptive evolution
Mutation rate is a key determinant of the pace as well as outcome of
evolution, and variability in this rate has been shown in different scenarios
to play a key role in evolutionary adaptation and resistance evolution under
stress caused by selective pressure. Here we investigate the dynamics of
resistance fixation in a bacterial population with variable mutation rates and
show that evolutionary outcomes are most sensitive to mutation rate variations
when the population is subject to environmental and demographic conditions that
suppress the evolutionary advantage of high-fitness subpopulations. By directly
mapping a biophysical fitness function to the system-level dynamics of the
population we show that both low and very high, but not intermediate, levels of
stress in the form of an antibiotic result in a disproportionate effect of
hypermutation on resistance fixation. We demonstrate how this behavior is
directly tied to the extent of genetic hitchhiking in the system, the
propagation of high-mutation rate cells through association with high-fitness
mutations. Our results indicate a substantial role for mutation rate
flexibility in the evolution of antibiotic resistance under conditions that
present a weak advantage over wildtype to resistant cells
Thermodynamics of the Hairpin Ribozyme from All-Atom Simulations
The structure of the self-cleaving hairpin ribozyme is well characterized,
and its folding has been examined in bulk and by single-molecule fluorescence,
establishing the importance of cations, especially magnesium in the stability
of the native fold. Here we describe the first all-atom folding simulations of
the hairpin ribozyme, using a version of a Go potential with separate secondary
and tertiary structure energetic contributions. The ratio of tertiary/secondary
interaction energies serves as a proxy for non-specific cation binding: a high
ratio corresponds to a high concentration, while a low one mimics low
concentration. By studying the unfolding behavior of the RNA over a range of
temperature and tertiary/secondary energies, a three-state phase diagram
emerges, with folded, unfolded (coil) and transient folding/unfolding tertiary
structure species. The thermodynamics were verified by paired folding
simulations in each region of the phase diagram. The three phase behaviors
correspond with experimentally observed states, so this simple model captures
the essential aspect of thermodynamics in RNA folding
Understanding hierarchical protein evolution from first principles
We propose a model that explains the hierarchical organization of proteins in
fold families. The model, which is based on the evolutionary selection of
proteins by their native state stability, reproduces patterns of amino acids
conserved across protein families. Due to its dynamic nature, the model sheds
light on the evolutionary time scales. By studying the relaxation of the
correlation function between consecutive mutations at a given position in
proteins, we observe separation of the evolutionary time scales: at the short
time intervals families of proteins with similar sequences and structures are
formed, while at long time intervals the families of structurally similar
proteins that have low sequence similarity are formed. We discuss the
evolutionary implications of our model. We provide a ``profile'' solution to
our model and find agreement between predicted patterns of conserved amino
acids and those actually observed in nature.Comment: 25 pages, 17 figure
Geometric and physical considerations for realistic protein models
Protein structure is generally conceptualized as the global arrangement or of
smaller, local motifs of helices, sheets, and loops. These regular, recurring
secondary structural elements have well-understood and standardized definitions
in terms of amino acid backbone geometry and the manner in which hydrogen
bonding requirements are satisfied. Recently, "tube" models have been proposed
to explain protein secondary structure in terms of the geometrically optimal
packing of a featureless cylinder. However, atomically detailed simulations
demonstrate that such packing considerations alone are insufficient for
defining secondary structure; both excluded volume and hydrogen bonding must be
explicitly modeled for helix formation. These results have fundamental
implications for the construction and interpretation of realistic and
meaningful biomacromolecular models
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