7,401 research outputs found
Simultaneous Coherent Structure Coloring facilitates interpretable clustering of scientific data by amplifying dissimilarity
The clustering of data into physically meaningful subsets often requires
assumptions regarding the number, size, or shape of the subgroups. Here, we
present a new method, simultaneous coherent structure coloring (sCSC), which
accomplishes the task of unsupervised clustering without a priori guidance
regarding the underlying structure of the data. sCSC performs a sequence of
binary splittings on the dataset such that the most dissimilar data points are
required to be in separate clusters. To achieve this, we obtain a set of
orthogonal coordinates along which dissimilarity in the dataset is maximized
from a generalized eigenvalue problem based on the pairwise dissimilarity
between the data points to be clustered. This sequence of bifurcations produces
a binary tree representation of the system, from which the number of clusters
in the data and their interrelationships naturally emerge. To illustrate the
effectiveness of the method in the absence of a priori assumptions, we apply it
to three exemplary problems in fluid dynamics. Then, we illustrate its capacity
for interpretability using a high-dimensional protein folding simulation
dataset. While we restrict our examples to dynamical physical systems in this
work, we anticipate straightforward translation to other fields where existing
analysis tools require ad hoc assumptions on the data structure, lack the
interpretability of the present method, or in which the underlying processes
are less accessible, such as genomics and neuroscience
Protein folding disorders: Toward a basic biological paradigm
Mechanistic 'physics' models of protein folding fail to account for the observed spectrum of protein folding and aggregation disorders, suggesting that a more appropriately biological paradigm will be needed for understanding the etiology, prevention, and treatment of these diseases
Structural Prediction of Protein–Protein Interactions by Docking: Application to Biomedical Problems
A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.Spanish Ministry of Economy grant number BIO2016-79960-R; D.B.B. is supported by a
predoctoral fellowship from CONACyT; M.R. is supported by an FPI fellowship from the
Severo Ochoa program. We are grateful to the Joint BSC-CRG-IRB Programme in
Computational Biology.Peer ReviewedPostprint (author's final draft
A variational approach to modeling slow processes in stochastic dynamical systems
The slow processes of metastable stochastic dynamical systems are difficult
to access by direct numerical simulation due the sampling problem. Here, we
suggest an approach for modeling the slow parts of Markov processes by
approximating the dominant eigenfunctions and eigenvalues of the propagator. To
this end, a variational principle is derived that is based on the maximization
of a Rayleigh coefficient. It is shown that this Rayleigh coefficient can be
estimated from statistical observables that can be obtained from short
distributed simulations starting from different parts of state space. The
approach forms a basis for the development of adaptive and efficient
computational algorithms for simulating and analyzing metastable Markov
processes while avoiding the sampling problem. Since any stochastic process
with finite memory can be transformed into a Markov process, the approach is
applicable to a wide range of processes relevant for modeling complex
real-world phenomena
Accurate and efficient description of protein vibrational dynamics: comparing molecular dynamics and Gaussian models
Current all-atom potential based molecular dynamics (MD) allow the
identification of a protein's functional motions on a wide-range of
time-scales, up to few tens of ns. However, functional large scale motions of
proteins may occur on a time-scale currently not accessible by all-atom
potential based molecular dynamics. To avoid the massive computational effort
required by this approach several simplified schemes have been introduced. One
of the most satisfactory is the Gaussian Network approach based on the energy
expansion in terms of the deviation of the protein backbone from its native
configuration. Here we consider an extension of this model which captures in a
more realistic way the distribution of native interactions due to the
introduction of effective sidechain centroids. Since their location is entirely
determined by the protein backbone, the model is amenable to the same exact and
computationally efficient treatment as previous simpler models. The ability of
the model to describe the correlated motion of protein residues in
thermodynamic equilibrium is established through a series of successful
comparisons with an extensive (14 ns) MD simulation based on the AMBER
potential of HIV-1 protease in complex with a peptide substrate. Thus, the
model presented here emerges as a powerful tool to provide preliminary, fast
yet accurate characterizations of proteins near-native motion.Comment: 14 pages 7 figure
Unfolding and refolding of cytochrome c driven by the interaction with lipid micelles
Binding of native cyt c to L-PG micelles leads to a partially unfolded conformation of cyt c. This micelle-bound state has no stable tertiary structure, but remains as -helical as native cyt c in solution. In contrast, binding of the acid-unfolded cyt c to L-PG micelles induces folding of the polypeptide, resulting in a similar helical state to that originated from the binding of native cyt c to L-PG micelles. Far-ultraviolet (UV) circular dichroism (CD) spectra showed that this common micelle-associated helical state (HL) has a native-like -helix content, but is highly expanded without a tightly packed hydrophobic core, as revealed by tryptophan fluorescence, near-UV, and Soret CD spectroscopy. The kinetics of the interaction of native and acid-unfolded cyt c was investigated by stopped-flow tryptophan fluorescence. Formation of HL from the native state requires the disruption of the tightly packed hydrophobic core in the native protein. This micelle-induced unfolding of cyt c occurs at a rate 0.1 s1, which is remarkably faster in the lipid environment compared with the expected rate of unfolding in solution. Refolding of acid-unfolded cyt c with L-PG micelles involves an early highly helical collapsed state formed during the burst phase (<3 ms), and the observed main kinetic event reports on the opening of this early compact intermediate prior to insertion into the lipid micelle
Hamiltonian dynamics of homopolymer chain models
The Hamiltonian dynamics of chains of nonlinearly coupled particles is
numerically investigated in two and three dimensions. Simple, off-lattice
homopolymer models are used to represent the interparticle potentials. Time
averages of observables numerically computed along dynamical trajectories are
found to reproduce results given by the statistical mechanics of homopolymer
models. The dynamical treatment, however, indicates a nontrivial transition
between regimes of slow and fast phase space mixing. Such a transition is
inaccessible to a statistical mechanical treatment and reflects a bimodality in
the relaxation of time averages to corresponding ensemble averages. It is also
found that a change in the energy dependence of the largest Lyapunov exponent
indicates the theta-transition between filamentary and globular polymer
configurations, clearly detecting the transition even for a finite number of
particles.Comment: 11 pages, 8 figures, accepted for publication in Physical Review
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