5,850 research outputs found
Protein Structure Determination Using Chemical Shifts
In this PhD thesis, a novel method to determine protein structures using
chemical shifts is presented.Comment: Univ Copenhagen PhD thesis (2014) in Biochemistr
Editorial overview: Folding and binding: In silico, in vitro and in cellula
The essence of any biological processes relies on the conformational states of macromolecules and their interactions. It comes therefore with no surprises that the study of folding and binding has been centre stage since the birth of structural biology. In this context, the collaborative efforts of experimen- talists and theoreticians have tremendously increased our current knowl- edge on macromolecular structure and recognition. Nevertheless, several challenges and open questions are still present and a multidisciplinary approach would appear the most appropriate means to shed light onto the mechanisms of folding and binding to the highest level of detail. This thematic issue brings together a collection of reviews describing our current understanding of folding and binding, looking at these fundamental pro- blems from a wide perspective ranging from the single molecule to the complexity of the living cell, drawing on approaches that span from compu- tational (in silico), to the test tube (in vitro) and cell cultures (in cellula)
Dissecting Ubiquitin Folding Using the Self-Organized Polymer Model
Folding of Ubiquitin (Ub) is investigated at low and neutral pH at different
temperatures using simulations of the coarse-grained Self-Organized-Polymer
model with side chains. The calculated radius of gyration, showing dramatic
variations with pH, is in excellent agreement with scattering experiments. At
Ub folds in a two-state manner at low and neutral pH. Clustering analysis
of the conformations sampled in equilibrium folding trajectories at , with
multiple transitions between the folded and unfolded states, show a network of
metastable states connecting the native and unfolded states. At low and neutral
pH, Ub folds with high probability through a preferred set of conformations
resulting in a pH-dependent dominant folding pathway. Folding kinetics reveal
that Ub assembly at low pH occurs by multiple pathways involving a combination
of nucleation-collapse and diffusion collision mechanism. The mechanism by
which Ub folds is dictated by the stability of the key secondary structural
elements responsible for establishing long range contacts and collapse of Ub.
Nucleation collapse mechanism holds if the stability of these elements are
marginal, as would be the case at elevated temperatures. If the lifetimes
associated with these structured microdomains are on the order of hundreds of
then Ub folding follows the diffusion-collision mechanism with
intermediates many of which coincide with those found in equilibrium. Folding
at neutral pH is a sequential process with a populated intermediate resembling
that sampled at equilibrium. The transition state structures, obtained using a
analysis, are homogeneous and globular with most of the secondary
and tertiary structures being native-like. Many of our findings are not only in
agreement with experiments but also provide missing details not resolvable in
standard experiments
Statistical modeling of RNA structure profiling experiments enables parsimonious reconstruction of structure landscapes.
RNA plays key regulatory roles in diverse cellular processes, where its functionality often derives from folding into and converting between structures. Many RNAs further rely on co-existence of alternative structures, which govern their response to cellular signals. However, characterizing heterogeneous landscapes is difficult, both experimentally and computationally. Recently, structure profiling experiments have emerged as powerful and affordable structure characterization methods, which improve computational structure prediction. To date, efforts have centered on predicting one optimal structure, with much less progress made on multiple-structure prediction. Here, we report a probabilistic modeling approach that predicts a parsimonious set of co-existing structures and estimates their abundances from structure profiling data. We demonstrate robust landscape reconstruction and quantitative insights into structural dynamics by analyzing numerous data sets. This work establishes a framework for data-directed characterization of structure landscapes to aid experimentalists in performing structure-function studies
A self-learning algorithm for biased molecular dynamics
A new self-learning algorithm for accelerated dynamics, reconnaissance
metadynamics, is proposed that is able to work with a very large number of
collective coordinates. Acceleration of the dynamics is achieved by
constructing a bias potential in terms of a patchwork of one-dimensional,
locally valid collective coordinates. These collective coordinates are obtained
from trajectory analyses so that they adapt to any new features encountered
during the simulation. We show how this methodology can be used to enhance
sampling in real chemical systems citing examples both from the physics of
clusters and from the biological sciences.Comment: 6 pages, 5 figures + 9 pages of supplementary informatio
Assessing Protein Conformational Sampling Methods Based on Bivariate Lag-Distributions of Backbone Angles
Despite considerable progress in the past decades, protein structure prediction remains one of the major unsolved problems in computational biology. Angular-sampling-based methods have been extensively studied recently due to their ability to capture the continuous conformational space of protein structures. The literature has focused on using a variety of parametric models of the sequential dependencies between angle pairs along the protein chains. In this article, we present a thorough review of angular-sampling-based methods by assessing three main questions: What is the best distribution type to model the protein angles? What is a reasonable number of components in a mixture model that should be considered to accurately parameterize the joint distribution of the angles? and What is the order of the local sequence–structure dependency that should be considered by a prediction method? We assess the model fits for different methods using bivariate lag-distributions of the dihedral/planar angles. Moreover, the main information across the lags can be extracted using a technique called Lag singular value decomposition (LagSVD), which considers the joint distribution of the dihedral/planar angles over different lags using a nonparametric approach and monitors the behavior of the lag-distribution of the angles using singular value decomposition. As a result, we developed graphical tools and numerical measurements to compare and evaluate the performance of different model fits. Furthermore, we developed a web-tool (http://www.stat.tamu.edu/∼madoliat/LagSVD) that can be used to produce informative animations
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PATTERNA: transcriptome-wide search for functional RNA elements via structural data signatures.
Establishing a link between RNA structure and function remains a great challenge in RNA biology. The emergence of high-throughput structure profiling experiments is revolutionizing our ability to decipher structure, yet principled approaches for extracting information on structural elements directly from these data sets are lacking. We present PATTERNA, an unsupervised pattern recognition algorithm that rapidly mines RNA structure motifs from profiling data. We demonstrate that PATTERNA detects motifs with an accuracy comparable to commonly used thermodynamic models and highlight its utility in automating data-directed structure modeling from large data sets. PATTERNA is versatile and compatible with diverse profiling techniques and experimental conditions
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