15,049 research outputs found
REinforcement learning based Adaptive samPling: REAPing Rewards by Exploring Protein Conformational Landscapes
One of the key limitations of Molecular Dynamics simulations is the
computational intractability of sampling protein conformational landscapes
associated with either large system size or long timescales. To overcome this
bottleneck, we present the REinforcement learning based Adaptive samPling
(REAP) algorithm that aims to efficiently sample conformational space by
learning the relative importance of each reaction coordinate as it samples the
landscape. To achieve this, the algorithm uses concepts from the field of
reinforcement learning, a subset of machine learning, which rewards sampling
along important degrees of freedom and disregards others that do not facilitate
exploration or exploitation. We demonstrate the effectiveness of REAP by
comparing the sampling to long continuous MD simulations and least-counts
adaptive sampling on two model landscapes (L-shaped and circular), and
realistic systems such as alanine dipeptide and Src kinase. In all four
systems, the REAP algorithm consistently demonstrates its ability to explore
conformational space faster than the other two methods when comparing the
expected values of the landscape discovered for a given amount of time. The key
advantage of REAP is on-the-fly estimation of the importance of collective
variables, which makes it particularly useful for systems with limited
structural information
The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein
The folding pathway and rate coefficients of the folding of a knotted protein
are calculated for a potential energy function with minimal energetic
frustration. A kinetic transition network is constructed using the discrete
path sampling approach, and the resulting potential energy surface is
visualized by constructing disconnectivity graphs. Owing to topological
constraints, the low-lying portion of the landscape consists of three distinct
regions, corresponding to the native knotted state and to configurations where
either the N- or C-terminus is not yet folded into the knot. The fastest
folding pathways from denatured states exhibit early formation of the
N-terminus portion of the knot and a rate-determining step where the C-terminus
is incorporated. The low-lying minima with the N-terminus knotted and the
C-terminus free therefore constitute an off-pathway intermediate for this
model. The insertion of both the N- and C-termini into the knot occur late in
the folding process, creating large energy barriers that are the rate limiting
steps in the folding process. When compared to other protein folding proteins
of a similar length, this system folds over six orders of magnitude more
slowly.Comment: 19 page
Exploring the Free Energy Landscape: From Dynamics to Networks and Back
The knowledge of the Free Energy Landscape topology is the essential key to
understand many biochemical processes. The determination of the conformers of a
protein and their basins of attraction takes a central role for studying
molecular isomerization reactions. In this work, we present a novel framework
to unveil the features of a Free Energy Landscape answering questions such as
how many meta-stable conformers are, how the hierarchical relationship among
them is, or what the structure and kinetics of the transition paths are.
Exploring the landscape by molecular dynamics simulations, the microscopic data
of the trajectory are encoded into a Conformational Markov Network. The
structure of this graph reveals the regions of the conformational space
corresponding to the basins of attraction. In addition, handling the
Conformational Markov Network, relevant kinetic magnitudes as dwell times or
rate constants, and the hierarchical relationship among basins, complete the
global picture of the landscape. We show the power of the analysis studying a
toy model of a funnel-like potential and computing efficiently the conformers
of a short peptide, the dialanine, paving the way to a systematic study of the
Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press
The physiology of movement
Movement, from foraging to migration, is known to be under the influence of the environment. The translation of environmental cues to individual movement decision making is determined by an individual's internal state and anticipated to balance costs and benefits. General body condition, metabolic and hormonal physiology mechanistically underpin this internal state. These physiological determinants are tightly, and often genetically linked with each other and hence central to a mechanistic understanding of movement. We here synthesise the available evidence of the physiological drivers and signatures of movement and review (1) how physiological state as measured in its most coarse way by body condition correlates with movement decisions during foraging, migration and dispersal, (2) how hormonal changes underlie changes in these movement strategies and (3) how these can be linked to molecular pathways. We reveale that a high body condition facilitates the efficiency of routine foraging, dispersal and migration. Dispersal decision making is, however, in some cases stimulated by a decreased individual condition. Many of the biotic and abiotic stressors that induce movement initiate a physiological cascade in vertebrates through the production of stress hormones. Movement is therefore associated with hormone levels in vertebrates but also insects, often in interaction with factors related to body or social condition. The underlying molecular and physiological mechanisms are currently studied in few model species, and show -in congruence with our insights on the role of body condition- a central role of energy metabolism during glycolysis, and the coupling with timing processes during migration. Molecular insights into the physiological basis of movement remain, however, highly refractory. We finalise this review with a critical reflection on the importance of these physiological feedbacks for a better mechanistic understanding of movement and its effects on ecological dynamics at all levels of biological organization
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