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The efficient calculation of rare-event kinetics in complex dynamical systems, such as the rate and pathways of ligand dissociation from a protein, is a generally unsolved problem. Markov state models can systematically integrate ensembles of short simulations and thus effectively parallelize the computational effort, but the rare events of interest still need to be spontaneously sampled in the data. Enhanced sampling approaches, such as parallel tempering or umbrella sampling, can accelerate the computation of equilibrium expectations massively - but sacrifice the ability to compute dynamical expectations. In this work we establish a principle to combine knowledge of the equilibrium distribution with kinetics from fast downhill relaxation trajectories using reversible Markov models. This approach is general as it does not invoke any specific dynamical model, and can provide accurate estimates of the rare event kinetics. Large gains in sampling efficiency can be achieved whenever one direction of the process occurs more rapid than its reverse, making the approach especially attractive for downhill processes such as folding and binding in biomolecules.
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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.
Estimating the probability of rare failure events is an essential step in the reliability assessment of engineering systems. Computing this failure probability for complex non-linear systems is challenging, and has recently spurred the development of active-learning reliability methods. These methods approximate the limit-state function (LSF) using surrogate models trained with a sequentially enriched set of model evaluations. A recently proposed method called stochastic spectral embedding (SSE) aims to improve the local approximation accuracy of global, spectral surrogate modelling techniques by sequentially embedding local residual expansions in subdomains of the input space. In this work we apply SSE to the LSF, giving rise to a stochastic spectral embedding-based reliability (SSER) method. The resulting partition of the input space decomposes the failure probability into a set of easy-to-compute domain-wise failure probabilities. We propose a set of modifications that tailor the algorithm to efficiently solve rare event estimation problems. These modifications include specialized refinement domain selection, partitioning and enrichment strategies. We showcase the algorithm performance on four benchmark problems of various dimensionality and complexity in the LSF.
We explore past and recent developments in rare-event probability estimation with a particular focus on a novel Monte Carlo technique Empirical Likelihood Maximization (ELM). This is a versatile method that involves sampling from a sequence of densities using MCMC and maximizing an empirical likelihood. The quantity of interest, the probability of a given rare-event, is estimated by solving a convex optimization program related to likelihood maximization. Numerical experiments are performed using this new technique and benchmarks are given against existing robust algorithms and estimators.
In this paper, we study a two-lane totally asymmetric simple exclusion process (TASEP) coupled with random attachment and detachment of particles (Langmuir kinetics) in both lanes under open boundary conditions. Our model can describe the directed motion of molecular motors, attachment and detachment of motors, and free inter-lane transition of motors between filaments. In this paper, we focus on some finite-size effects of the system because normally the sizes of most real systems are finite and small (e.g., size $leq 10,000$). A special finite-size effect of the two-lane system has been observed, which is that the density wall moves left first and then move towards the right with the increase of the lane-changing rate. We called it the jumping effect. We find that increasing attachment and detachment rates will weaken the jumping effect. We also confirmed that when the size of the two-lane system is large enough, the jumping effect disappears, and the two-lane system has a similar density profile to a single-lane TASEP coupled with Langmuir kinetics. Increasing lane-changing rates has little effect on density and current after the density reaches maximum. Also, lane-changing rate has no effect on density profiles of a two-lane TASEP coupled with Langmuir kinetics at a large attachment/detachment rate and/or a large system size. Mean-field approximation is presented and it agrees with our Monte Carlo simulations.
The role of proton tunneling in biological catalysis is investigated here within the frameworks of quantum information theory and thermodynamics. We consider the quantum correlations generated through two hydrogen bonds between a substrate and a prototypical enzyme that first catalyzes the tautomerization of the substrate to move on to a subsequent catalysis, and discuss how the enzyme can derive its catalytic potency from these correlations. In particular, we show that classical changes induced in the binding site of the enzyme spreads the quantum correlations among all of the four hydrogen-bonded atoms thanks to the directionality of hydrogen bonds. If the enzyme rapidly returns to its initial state after the binding stage, the substrate ends in a new transition state corresponding to a quantum superposition. Open quantum system dynamics can then naturally drive the reaction in the forward direction from the major tautomeric form to the minor tautomeric form without needing any additional catalytic activity. We find that in this scenario the enzyme lowers the activation energy so much that there is no energy barrier left in the tautomerization, even if the quantum correlations quickly decay.
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