2,031 research outputs found
Hamiltonian replica-exchange in GROMACS: a flexible implementation
A simple and general implementation of Hamiltonian replica exchange for the popular molecular-dynamics software GROMACS is presented. In this implementation, arbitrarily different Hamiltonians can be used for the different replicas without incurring in any significant performance penalty. The implementation was validated on a simple toy model - alanine dipeptide in water - and applied to study the rearrangement of an RNA tetraloop, where it was used to compare recently proposed force-field corrections
Linking thermodynamics and measurements of protein stability
We review the background, theory and general equations for the analysis of
equilibrium protein unfolding experiments, focusing on denaturant and
heat-induced unfolding. The primary focus is on the thermodynamics of
reversible folding/unfolding transitions and the experimental methods that are
available for extracting thermodynamic parameters. We highlight the importance
of modelling both how the folding equilibrium depends on a perturbing variable
such as temperature or denaturant concentration, and the importance of
modelling the baselines in the experimental observables.Comment: 21 pages, 5 figure
Frequency adaptive metadynamics for the calculation of rare-event kinetics
The ability to predict accurate thermodynamic and kinetic properties in
biomolecular systems is of both scientific and practical utility. While both
remain very difficult, predictions of kinetics are particularly difficult
because rates, in contrast to free energies, depend on the route taken and are
thus not amenable to all enhanced sampling methods. It has recently been
demonstrated that it is possible to recover kinetics through so called
`infrequent metadynamics' simulations, where the simulations are biased in a
way that minimally corrupts the dynamics of moving between metastable states.
This method, however, requires the bias to be added slowly, thus hampering
applications to processes with only modest separations of timescales. Here we
present a frequency-adaptive strategy which bridges normal and infrequent
metadynamics. We show that this strategy can improve the precision and accuracy
of rate calculations at fixed computational cost, and should be able to extend
rate calculations for much slower kinetic processes.Comment: 15 pages, 2 figures, 2 table
Accelerating delayed-acceptance Markov chain Monte Carlo algorithms
Delayed-acceptance Markov chain Monte Carlo (DA-MCMC) samples from a
probability distribution via a two-stages version of the Metropolis-Hastings
algorithm, by combining the target distribution with a "surrogate" (i.e. an
approximate and computationally cheaper version) of said distribution. DA-MCMC
accelerates MCMC sampling in complex applications, while still targeting the
exact distribution. We design a computationally faster, albeit approximate,
DA-MCMC algorithm. We consider parameter inference in a Bayesian setting where
a surrogate likelihood function is introduced in the delayed-acceptance scheme.
When the evaluation of the likelihood function is computationally intensive,
our scheme produces a 2-4 times speed-up, compared to standard DA-MCMC.
However, the acceleration is highly problem dependent. Inference results for
the standard delayed-acceptance algorithm and our approximated version are
similar, indicating that our algorithm can return reliable Bayesian inference.
As a computationally intensive case study, we introduce a novel stochastic
differential equation model for protein folding data.Comment: 40 pages, 21 figures, 10 table
Mapping transiently formed and sparsely populated conformations on a complex energy landscape
Determining the structures, kinetics, thermodynamics and mechanisms that underlie conformational exchange processes in proteins remains extremely difficult. Only in favourable cases is it possible to provide atomic-level descriptions of sparsely populated and transiently formed alternative conformations. Here we benchmark the ability of enhanced-sampling molecular dynamics simulations to determine the free energy landscape of the L99A cavity mutant of T4 lysozyme. We find that the simulations capture key properties previously measured by NMR relaxation dispersion methods including the structure of a minor conformation, the kinetics and thermodynamics of conformational exchange, and the effect of mutations. We discover a new tunnel that involves the transient exposure towards the solvent of an internal cavity, and show it to be relevant for ligand escape. Together, our results provide a comprehensive view of the structural landscape of a protein, and point forward to studies of conformational exchange in systems that are less characterized experimentally. DOI: http://dx.doi.org/10.7554/eLife.17505.00
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