654 research outputs found
Onsager-Machlup action-based path sampling and its combination with replica exchange for diffusive and multiple pathways
For sampling multiple pathways in a rugged energy landscape, we propose a
novel action-based path sampling method using the Onsager-Machlup action
functional. Inspired by the Fourier-path integral simulation of a quantum
mechanical system, a path in Cartesian space is transformed into that in
Fourier space, and an overdamped Langevin equation is derived for the Fourier
components to achieve a canonical ensemble of the path at a finite temperature.
To avoid "path trapping" around an initially guessed path, the path sampling
method is further combined with a powerful sampling technique, the replica
exchange method. The principle and algorithm of our method is numerically
demonstrated for a model two-dimensional system with a bifurcated potential
landscape. The results are compared with those of conventional transition path
sampling and the equilibrium theory, and the error due to path discretization
is also discussed.Comment: 20 pages, 5 figures, submitted to J. Chem. Phy
Self-learning Multiscale Simulation for Achieving High Accuracy and High Efficiency Simultaneously
We propose a new multi-scale molecular dynamics simulation method which can
achieve high accuracy and high sampling efficiency simultaneously without
aforehand knowledge of the coarse grained (CG) potential and test it for a
biomolecular system. Based on the resolution exchange simulations between
atomistic and CG replicas, a self-learning strategy is introduced to
progressively improve the CG potential by an iterative way. Two tests show
that, the new method can rapidly improve the CG potential and achieve efficient
sampling even starting from an unrealistic CG potential. The resulting free
energy agreed well with exact result and the convergence by the method was much
faster than that by the replica exchange method. The method is generic and can
be applied to many biological as well as non-biological problems.Comment: 14 pages, 6 figure
Directly measuring single molecule heterogeneity using force spectroscopy
One of the most intriguing results of single molecule experiments on proteins
and nucleic acids is the discovery of functional heterogeneity: the observation
that complex cellular machines exhibit multiple, biologically active
conformations. The structural differences between these conformations may be
subtle, but each distinct state can be remarkably long-lived, with random
interconversions between states occurring only at macroscopic timescales,
fractions of a second or longer. Though we now have proof of functional
heterogeneity in a handful of systems---enzymes, motors, adhesion
complexes---identifying and measuring it remains a formidable challenge. Here
we show that evidence of this phenomenon is more widespread than previously
known, encoded in data collected from some of the most well-established single
molecule techniques: AFM or optical tweezer pulling experiments. We present a
theoretical procedure for analyzing distributions of rupture/unfolding forces
recorded at different pulling speeds. This results in a single parameter,
quantifying the degree of heterogeneity, and also leads to bounds on the
equilibration and conformational interconversion timescales. Surveying ten
published datasets, we find heterogeneity in five of them, all with
interconversion rates slower than 10 s. Moreover, we identify two
systems where additional data at realizable pulling velocities is likely to
find a theoretically predicted, but so far unobserved cross-over regime between
heterogeneous and non-heterogeneous behavior. The significance of this regime
is that it will allow far more precise estimates of the slow conformational
switching times, one of the least understood aspects of functional
heterogeneity.Comment: Main text: 13 pages, 6 figures; SI: 9 pages, 6 figure
Recurrence quantification analysis as a tool for the characterization of molecular dynamics simulations
A molecular dynamics simulation of a Lennard-Jones fluid, and a trajectory of
the B1 immunoglobulin G-binding domain of streptococcal protein G (B1-IgG)
simulated in water are analyzed by recurrence quantification, which is
noteworthy for its independence from stationarity constraints, as well as its
ability to detect transients, and both linear and nonlinear state changes. The
results demonstrate the sensitivity of the technique for the discrimination of
phase sensitive dynamics. Physical interpretation of the recurrence measures is
also discussed.Comment: 7 pages, 8 figures, revtex; revised for review for Phys. Rev. E
(clarifications and expansion of discussion)-- addition of the 8 postscript
figures previously omitted, but unchanged from version
Monte Carlo, harmonic approximation, and coarse-graining approaches for enhanced sampling of biomolecular structure
The rugged energy landscape of biomolecules and associated large-scale conformational changes have triggered the development of many innovative enhanced sampling methods, either based or not based on molecular dynamics (MD) simulations. Surveyed here are methods in the latter class - including Monte Carlo methods, harmonic approximations, and coarse graining - many of which yield valuable conformational insights into biomolecular structure and flexibility, despite altered kinetics. MD-based methods are surveyed in an upcoming issue of F1000 Biology Reports
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