14,460 research outputs found
Combining Coarse-Grained Protein Models with Replica-Exchange All-Atom Molecular Dynamics
We describe a combination of all-atom simulations with CABS, a
well-established coarse-grained protein modeling tool, into a single multiscale
protocol. The simulation method has been tested on the C-terminal beta hairpin
of protein G, a model system of protein folding. After reconstructing atomistic
details, conformations derived from the CABS simulation were subjected to
replica-exchange molecular dynamics simulations with OPLS-AA and AMBER99sb
force fields in explicit solvent. Such a combination accelerates system
convergence several times in comparison with all-atom simulations starting from
the extended chain conformation, demonstrated by the analysis of melting
curves, the number of native-like conformations as a function of time and
secondary structure propagation. The results strongly suggest that the proposed
multiscale method could be an efficient and accurate tool for high-resolution
studies of protein folding dynamics in larger systems.Comment: 12 pages, 4 figure
Bridge helix bending promotes RNA polymerase II backtracking through a critical and conserved threonine residue.
The dynamics of the RNA polymerase II (Pol II) backtracking process is poorly understood. We built a Markov State Model from extensive molecular dynamics simulations to identify metastable intermediate states and the dynamics of backtracking at atomistic detail. Our results reveal that Pol II backtracking occurs in a stepwise mode where two intermediate states are involved. We find that the continuous bending motion of the Bridge helix (BH) serves as a critical checkpoint, using the highly conserved BH residue T831 as a sensing probe for the 3'-terminal base paring of RNA:DNA hybrid. If the base pair is mismatched, BH bending can promote the RNA 3'-end nucleotide into a frayed state that further leads to the backtracked state. These computational observations are validated by site-directed mutagenesis and transcript cleavage assays, and provide insights into the key factors that regulate the preferences of the backward translocation
Simulating rare events using a Weighted Ensemble-based string method
We introduce an extension to the Weighted Ensemble (WE) path sampling method
to restrict sampling to a one dimensional path through a high dimensional phase
space. Our method, which is based on the finite-temperature string method,
permits efficient sampling of both equilibrium and non-equilibrium systems.
Sampling obtained from the WE method guides the adaptive refinement of a
Voronoi tessellation of order parameter space, whose generating points, upon
convergence, coincide with the principle reaction pathway. We demonstrate the
application of this method to several simple, two-dimensional models of driven
Brownian motion and to the conformational change of the nitrogen regulatory
protein C receiver domain using an elastic network model. The simplicity of the
two-dimensional models allows us to directly compare the efficiency of the WE
method to conventional brute force simulations and other path sampling
algorithms, while the example of protein conformational change demonstrates how
the method can be used to efficiently study transitions in the space of many
collective variables
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