3,667 research outputs found
Exploration of Reaction Pathways and Chemical Transformation Networks
For the investigation of chemical reaction networks, the identification of
all relevant intermediates and elementary reactions is mandatory. Many
algorithmic approaches exist that perform explorations efficiently and
automatedly. These approaches differ in their application range, the level of
completeness of the exploration, as well as the amount of heuristics and human
intervention required. Here, we describe and compare the different approaches
based on these criteria. Future directions leveraging the strengths of chemical
heuristics, human interaction, and physical rigor are discussed.Comment: 48 pages, 4 figure
Computational structure‐based drug design: Predicting target flexibility
The role of molecular modeling in drug design has experienced a significant revamp in the last decade. The increase in computational resources and molecular models, along with software developments, is finally introducing a competitive advantage in early phases of drug discovery. Medium and small companies with strong focus on computational chemistry are being created, some of them having introduced important leads in drug design pipelines. An important source for this success is the extraordinary development of faster and more efficient techniques for describing flexibility in three‐dimensional structural molecular modeling. At different levels, from docking techniques to atomistic molecular dynamics, conformational sampling between receptor and drug results in improved predictions, such as screening enrichment, discovery of transient cavities, etc. In this review article we perform an extensive analysis of these modeling techniques, dividing them into high and low throughput, and emphasizing in their application to drug design studies. We finalize the review with a section describing our Monte Carlo method, PELE, recently highlighted as an outstanding advance in an international blind competition and industrial benchmarks.We acknowledge the BSC-CRG-IRB Joint Research Program in Computational Biology. This work was supported by a grant
from the Spanish Government CTQ2016-79138-R.J.I. acknowledges support from SVP-2014-068797, awarded by the Spanish Government.Peer ReviewedPostprint (author's final draft
Structure and mechanical characterization of DNA i-motif nanowires by molecular dynamics simulation
We studied the structure and mechanical properties of DNA i-motif nanowires
by means of molecular dynamics computer simulations. We built up to 230 nm long
nanowires, based on a repeated TC5 sequence from crystallographic data, fully
relaxed and equilibrated in water. The unusual stacked C*C+ stacked structure,
formed by four ssDNA strands arranged in an intercalated tetramer, is here
fully characterized both statically and dynamically. By applying stretching,
compression and bending deformation with the steered molecular dynamics and
umbrella sampling methods, we extract the apparent Young's and bending moduli
of the nanowire, as wel as estimates for the tensile strength and persistence
length. According to our results, the i-motif nanowire shares similarities with
structural proteins, as far as its tensile stiffness, but is closer to nucleic
acids and flexible proteins, as far as its bending rigidity is concerned.
Furthermore, thanks to its very thin cross section, the apparent tensile
toughness is close to that of a metal. Besides their yet to be clarified
biological significance, i-motif nanowires may qualify as interesting
candidates for nanotechnology templates, due to such outstanding mechanical
properties.Comment: 25 pages, 1 table, 7 figures; preprint submitted to Biophysical
Journa
Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.
Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate
Steering in computational science: mesoscale modelling and simulation
This paper outlines the benefits of computational steering for high
performance computing applications. Lattice-Boltzmann mesoscale fluid
simulations of binary and ternary amphiphilic fluids in two and three
dimensions are used to illustrate the substantial improvements which
computational steering offers in terms of resource efficiency and time to
discover new physics. We discuss details of our current steering
implementations and describe their future outlook with the advent of
computational grids.Comment: 40 pages, 11 figures. Accepted for publication in Contemporary
Physic
Multidimensional integration through Markovian sampling under steered function morphing: a physical guise from statistical mechanics
We present a computational strategy for the evaluation of multidimensional
integrals on hyper-rectangles based on Markovian stochastic exploration of the
integration domain while the integrand is being morphed by starting from an
initial appropriate profile. Thanks to an abstract reformulation of Jarzynski's
equality applied in stochastic thermodynamics to evaluate the free-energy
profiles along selected reaction coordinates via non-equilibrium
transformations, it is possible to cast the original integral into the
exponential average of the distribution of the pseudo-work (that we may term
"computational work") involved in doing the function morphing, which is
straightforwardly solved. Several tests illustrate the basic implementation of
the idea, and show its performance in terms of computational time, accuracy and
precision. The formulation for integrand functions with zeros and possible sign
changes is also presented. It will be stressed that our usage of Jarzynski's
equality shares similarities with a practice already known in statistics as
Annealed Importance Sampling (AIS), when applied to computation of the
normalizing constants of distributions. In a sense, here we dress the AIS with
its "physical" counterpart borrowed from statistical mechanics.Comment: 3 figures Supplementary Material (pdf file named "JEMDI_SI.pdf"
Free energy reconstruction from steered dynamics without post-processing
Various methods achieving importance sampling in ensembles of nonequilibrium
trajectories enable to estimate free energy differences and, by
maximum-likelihood post-processing, to reconstruct free energy landscapes.
Here, based on Bayes theorem, we propose a more direct method in which a
posterior likelihood function is used both to construct the steered dynamics
and to infer the contribution to equilibrium of all the sampled states. The
method is implemented with two steering schedules. First, using non-autonomous
steering, we calculate the migration barrier of the vacancy in Fe-alpha.
Second, using an autonomous scheduling related to metadynamics and equivalent
to temperature-accelerated molecular dynamics, we accurately reconstruct the
two-dimensional free energy landscape of the 38-atom Lennard-Jones cluster as a
function of an orientational bond-order parameter and energy, down to the
solid-solid structural transition temperature of the cluster and without
maximum-likelihood post-processing.Comment: Accepted manuscript in Journal of Computational Physics, 7 figure
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