The Experts below are selected from a list of 5484 Experts worldwide ranked by ideXlab platform
Michele Parrinello - One of the best experts on this subject based on the ideXlab platform.
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Metadynamics of paths
Physical Review Letters, 2020Co-Authors: Davide Mandelli, Michele Parrinello, Barak HirshbergAbstract:We present a method to sample reactive pathways via biased molecular dynamics simulations in trajectory space. We show that the use of enhanced sampling techniques enables unconstrained exploration of multiple reaction routes. Time correlation functions are conveniently computed via reweighted averages along a single trajectory and kinetic rates are accessed at no additional cost. These abilities are illustrated analyzing a model potential and the umbrella inversion of NH_{3} in water. The algorithm allows a parallel implementation and promises to be a powerful tool for the study of rare events.
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Rethinking Metadynamics: From Bias Potentials to Probability Distributions
The journal of physical chemistry letters, 2020Co-Authors: Michele Invernizzi, Michele ParrinelloAbstract:Metadynamics is an enhanced sampling method of great popularity, based on the on-the-fly construction of a bias potential that is a function of a selected number of collective variables. We propose...
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Combining Metadynamics and Integrated Tempering Sampling
The journal of physical chemistry letters, 2018Co-Authors: Yi Isaac Yang, Haiyang Niu, Michele ParrinelloAbstract:The simulation of rare events is one of the key problems in atomistic simulations. Toward its solution, a plethora of methods have been proposed. Here we combine two such methods: Metadynamics and integrated tempering sampling. In Metadynamics, the fluctuations of a carefully chosen collective variable are amplified, while in integrated tempering sampling the system is pushed to visit an approximately uniform interval of energies and allows exploring a range of temperatures in a single run. We describe our approach and apply it to the two prototypical systems a SN2 chemical reaction and to the freezing of silica. The combination of Metadynamics and integrated tempering sampling leads to a powerful method. In particular in the case of silica we have measured more than 1 order of magnitude acceleration.
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Frequency adaptive Metadynamics for the calculation of rare-event kinetics
The Journal of chemical physics, 2018Co-Authors: Yong Wang, Michele Parrinello, Pratyush Tiwary, Omar Valsson, Kresten Lindorff-larsenAbstract: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. For this reason, specific enhanced sampling methods are needed to calculate long-time scale kinetics. It has recently been demonstrated that it is possible to recover kinetics through the 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 time scales. 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.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. For this reason, specific enhanced sampling methods are needed to calculate long-time scale kinetics. It has recently been demonstrated that it is possible to recover kinetics through the 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 time scales. 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 a...
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a variational conformational dynamics approach to the selection of collective variables in Metadynamics
arXiv: Statistical Mechanics, 2017Co-Authors: Michele Parrinello, James MccartyAbstract:In this paper we combine two powerful computational techniques, well-tempered Metadynamics and time lagged independent component analysis. The aim is to develop a new tool for studying rare events and exploring complex free energy landscapes. Metadynamics is a well-established and widely used enhanced sampling method whose efficiency depends on an appropriate choice of collective variables. Often the initial choice is not optimal leading to slow convergence. However by analyzing the dynamics generated in one such a run with a time-lagged independent component analysis and the techniques recently developed in the area of conformational dynamics, we obtain much more efficient collective variables, that are also better capable of illuminating the physics of the system. We demonstrate the power of this approach in two paradigmatic examples.
Thomas Vogel - One of the best experts on this subject based on the ideXlab platform.
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molecular dynamics in the multicanonical ensemble equivalence of wang landau sampling statistical temperature molecular dynamics and Metadynamics
Journal of Chemical Theory and Computation, 2014Co-Authors: Christoph Junghans, Danny Perez, Thomas VogelAbstract:We show a direct formal relationship between the Wang-Landau iteration [PRL 86, 2050 (2001)], Metadynamics [PNAS 99, 12562 (2002)], and statistical temperature molecular dynamics (STMD) [PRL 97, 050601 (2006)] that are the major work-horses for sampling from generalized ensembles. We demonstrate that STMD, itself derived from the Wang-Landau method, can be made indistinguishable from Metadynamics. We also show that Gaussian kernels significantly improve the performance of STMD, highlighting the practical benefits of this improved formal understanding.
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Molecular Dynamics in the Multicanonical Ensemble: Equivalence of Wang-Landau Sampling, Statistical Temperature Molecular Dynamics, and Metadynamics
Journal of chemical theory and computation, 2014Co-Authors: Christoph Junghans, Danny Perez, Thomas VogelAbstract:We show direct formal relationship between the Wang-Landau iteration [PRL 86, 2050 (2001)], Metadynamics [PNAS 99, 12562 (2002)] and statistical temperature molecular dynamics [PRL 97, 050601 (2006)], the major Monte Carlo and molecular dynamics work-horses for sampling from a generalized, multicanonical ensemble. We demonstrate that statistical temperature molecular dynamics (which is formally derived from the Wang-Landau method), augmented by the introduction of kernel updates of the statistical temperature, generates dynamics which are indistinguishable from a corresponding Metadynamics simulation. We also show that the use of a Gaussian kernel significantly improves the performance of statistical temperature molecular dynamics, highlighting the practical benefits of this improved formal understanding.
Pratyush Tiwary - One of the best experts on this subject based on the ideXlab platform.
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can one trust kinetic and thermodynamic observables from biased Metadynamics simulations detailed quantitative benchmarks on millimolar drug fragment dissociation
bioRxiv, 2019Co-Authors: Debabrata Pramanik, Zachary Smith, Adam Kells, Pratyush TiwaryAbstract:Abstract Obtaining atomistic resolution of ligand dissociation from a protein is a much sought after experimental and computational challenge. Structural details of the dissociation process are in general hard to capture in experiments, while the relevant timescales are far beyond molecular dynamics (MD) simulations even with the most powerful super-computers. As such many different specialized enhanced sampling methods have been proposed that make it possible to efficiently calculate the dissociation mechanisms in protein-ligand systems. However, accurate benchmarks against long unbiased MD simulations are either not reported yet or simply not feasible due to the extremely long timescales. In this manuscript, we consider one such recent method “infrequent Metadynamics”, and benchmark in detail the various thermodynamics and kinetic information obtained from this method against extensive unbiased MD simulations for the dissociation dynamics of two different millimolar fragments from the protein FKBP in explicit water with residence times in nanoseconds to microseconds regime. We find that the Metadynamics approach gives the same binding free energy profile, dissociation pathway and ligand residence time as the unbiased MD, albeit using only 6 to 50 times lower computational resources. Furthermore, we demonstrate how the Metadynamics approach can self-consistently be used to ascertain whether the reweighted kinetic constants are reliable or not. We thus conclude that the answer to the question posed in the title of this manuscript is: statistically speaking, yes.
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Frequency adaptive Metadynamics for the calculation of rare-event kinetics
The Journal of chemical physics, 2018Co-Authors: Yong Wang, Michele Parrinello, Pratyush Tiwary, Omar Valsson, Kresten Lindorff-larsenAbstract: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. For this reason, specific enhanced sampling methods are needed to calculate long-time scale kinetics. It has recently been demonstrated that it is possible to recover kinetics through the 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 time scales. 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.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. For this reason, specific enhanced sampling methods are needed to calculate long-time scale kinetics. It has recently been demonstrated that it is possible to recover kinetics through the 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 time scales. 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 a...
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Enhancing Important Fluctuations: Rare Events and Metadynamics from a Conceptual Viewpoint
Annual review of physical chemistry, 2016Co-Authors: Omar Valsson, Pratyush Tiwary, Michele ParrinelloAbstract:Atomistic simulations play a central role in many fields of science. However, their usefulness is often limited by the fact that many systems are characterized by several metastable states separated by high barriers, leading to kinetic bottlenecks. Transitions between metastable states are thus rare events that occur on significantly longer timescales than one can simulate in practice. Numerous enhanced sampling methods have been introduced to alleviate this timescale problem, including methods based on identifying a few crucial order parameters or collective variables and enhancing the sampling of these variables. Metadynamics is one such method that has proven successful in a great variety of fields. Here we review the conceptual and theoretical foundations of Metadynamics. As demonstrated, Metadynamics is not just a practical tool but can also be considered an important development in the theory of statistical mechanics.
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de Broglie Swapping Metadynamics for Quantum and Classical Sampling.
Journal of chemical theory and computation, 2015Co-Authors: Marco Nava, Pratyush Tiwary, Ruge Quhe, Ferruccio Palazzesi, Michele ParrinelloAbstract:This paper builds on our previous work on Path Integral Metadynamics [Ruge et al. J. Chem. Theory Comput. 2015, 11, 1383] in which we have accelerated sampling in quantum systems described by Feynman’s Path Integrals using Metadynamics. We extend the scope of Path Integral Metadynamics by combining it with a replica exchange scheme in which artificially enhanced quantum effects play the same role as temperature does in parallel tempering. Our scheme can be adapted so as to be used in an ancillary way to sample systems described by classical statistical mechanics. Contrary to Metadynamics and many other sampling methods no collective variables need to be defined. The method in its two variants, quantum and classical, is tested in a number of examples.
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Path Integral Metadynamics.
Journal of chemical theory and computation, 2015Co-Authors: Ruge Quhe, Marco Nava, Pratyush Tiwary, Michele ParrinelloAbstract:We develop a new efficient approach for the simulation of static properties of quantum systems using path integral molecular dynamics in combination with Metadynamics. We use the isomorphism between a quantum system and a classical one in which a quantum particle is mapped into a ring polymer. A history dependent biasing potential is built as a function of the elastic energy of the isomorphic polymer. This enhances fluctuations in the shape and size of the necklace in a controllable manner and allows escaping deep energy minima in a limited computer time. In this way, we are able to sample high free energy regions and cross barriers, which would otherwise be insurmountable with unbiased methods. This substantially improves the ability of finding the global free energy minimum as well as exploring other metastable states. The performance of the new technique is demonstrated by illustrative applications on model potentials of varying complexity.
Christoph Junghans - One of the best experts on this subject based on the ideXlab platform.
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molecular dynamics in the multicanonical ensemble equivalence of wang landau sampling statistical temperature molecular dynamics and Metadynamics
Journal of Chemical Theory and Computation, 2014Co-Authors: Christoph Junghans, Danny Perez, Thomas VogelAbstract:We show a direct formal relationship between the Wang-Landau iteration [PRL 86, 2050 (2001)], Metadynamics [PNAS 99, 12562 (2002)], and statistical temperature molecular dynamics (STMD) [PRL 97, 050601 (2006)] that are the major work-horses for sampling from generalized ensembles. We demonstrate that STMD, itself derived from the Wang-Landau method, can be made indistinguishable from Metadynamics. We also show that Gaussian kernels significantly improve the performance of STMD, highlighting the practical benefits of this improved formal understanding.
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Molecular Dynamics in the Multicanonical Ensemble: Equivalence of Wang-Landau Sampling, Statistical Temperature Molecular Dynamics, and Metadynamics
Journal of chemical theory and computation, 2014Co-Authors: Christoph Junghans, Danny Perez, Thomas VogelAbstract:We show direct formal relationship between the Wang-Landau iteration [PRL 86, 2050 (2001)], Metadynamics [PNAS 99, 12562 (2002)] and statistical temperature molecular dynamics [PRL 97, 050601 (2006)], the major Monte Carlo and molecular dynamics work-horses for sampling from a generalized, multicanonical ensemble. We demonstrate that statistical temperature molecular dynamics (which is formally derived from the Wang-Landau method), augmented by the introduction of kernel updates of the statistical temperature, generates dynamics which are indistinguishable from a corresponding Metadynamics simulation. We also show that the use of a Gaussian kernel significantly improves the performance of statistical temperature molecular dynamics, highlighting the practical benefits of this improved formal understanding.
Gregory A. Voth - One of the best experts on this subject based on the ideXlab platform.
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Transition-Tempered Metadynamics Is a Promising Tool for Studying the Permeation of Drug-like Molecules through Membranes
Journal of chemical theory and computation, 2016Co-Authors: Rui Sun, James F. Dama, Jeffrey S. Tan, John P. Rose, Gregory A. VothAbstract:Metadynamics is an important enhanced sampling technique in molecular dynamics simulation to efficiently explore potential energy surfaces. The recently developed transition-tempered Metadynamics (TTMetaD) has been proven to converge asymptotically without sacrificing exploration of the collective variable space in the early stages of simulations, unlike other convergent Metadynamics (MetaD) methods. We have applied TTMetaD to study the permeation of drug-like molecules through a lipid bilayer to further investigate the usefulness of this method as applied to problems of relevance to medicinal chemistry. First, ethanol permeation through a lipid bilayer was studied to compare TTMetaD with nontempered Metadynamics and well-tempered Metadynamics. The bias energies computed from various Metadynamics simulations were compared to the potential of mean force calculated from umbrella sampling. Though all of the MetaD simulations agree with one another asymptotically, TTMetaD is able to predict the most accurate ...
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Exploring Valleys without Climbing Every Peak: More Efficient and Forgiving Metabasin Metadynamics via Robust On-the-Fly Bias Domain Restriction
Journal of chemical theory and computation, 2015Co-Authors: James F. Dama, Rui Sun, Glen M. Hocky, Gregory A. VothAbstract:Metadynamics is an enhanced sampling method designed to flatten free energy surfaces uniformly. However, the highest-energy regions are often irrelevant to study and dangerous to explore because systems often change irreversibly in unforeseen ways in response to driving forces in these regions, spoiling the sampling. Introducing an on-the-fly domain restriction allows Metadynamics to flatten only up to a specified energy level and no further, improving efficiency and safety while decreasing the pressure on practitioners to design collective variables that are robust to otherwise irrelevant high energy driving. This paper describes a new method that achieves this using sequential on-the-fly estimation of energy wells and redefinition of the Metadynamics hill shape, termed metabasin Metadynamics. The energy level may be defined a priori or relative to unknown barrier energies estimated on-the-fly. Altering only the hill ensures that the method is compatible with many other advances in Metadynamics methodolo...
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Transition-Tempered Metadynamics: Robust, Convergent Metadynamics via On-the-Fly Transition Barrier Estimation.
Journal of chemical theory and computation, 2014Co-Authors: James F. Dama, Michele Parrinello, Grant M. Rotskoff, Gregory A. VothAbstract:Well-tempered Metadynamics has proven to be a practical and efficient adaptive enhanced sampling method for the computational study of biomolecular and materials systems. However, choosing its tunable parameter can be challenging and requires balancing a trade-off between fast escape from local metastable states and fast convergence of an overall free energy estimate. In this article, we present a new smoothly convergent variant of Metadynamics, transition-tempered Metadynamics, that removes that trade-off and is more robust to changes in its own single tunable parameter, resulting in substantial speed and accuracy improvements. The new method is specifically designed to study state-to-state transitions in which the states of greatest interest are known ahead of time, but transition mechanisms are not. The design is guided by a picture of adaptive enhanced sampling as a means to increase dynamical connectivity of a model's state space until percolation between all points of interest is reached, and it uses the degree of dynamical percolation to automatically tune the convergence rate. We apply the new method to Brownian dynamics on 48 random 1D surfaces, blocked alanine dipeptide in vacuo, and aqueous myoglobin, finding that transition-tempered Metadynamics substantially and reproducibly improves upon well-tempered Metadynamics in terms of first barrier crossing rate, convergence rate, and robustness to the choice of tuning parameter. Moreover, the trade-off between first barrier crossing rate and convergence rate is eliminated: the new method drives escape from an initial metastable state as fast as Metadynamics without tempering, regardless of tuning.
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Well-tempered Metadynamics converges asymptotically.
Physical review letters, 2014Co-Authors: James F. Dama, Michele Parrinello, Gregory A. VothAbstract:Metadynamics is a versatile and capable enhanced sampling method for the computational study of soft matter materials and biomolecular systems. However, over a decade of application and several attempts to give this adaptive umbrella sampling method a firm theoretical grounding prove that a rigorous convergence analysis is elusive. This Letter describes such an analysis, demonstrating that well-tempered Metadynamics converges to the final state it was designed to reach and, therefore, that the simple formulas currently used to interpret the final converged state of tempered Metadynamics are correct and exact. The results do not rely on any assumption that the collective variable dynamics are effectively Brownian or any idealizations of the hill deposition function; instead, they suggest new, more permissive criteria for the method to be well behaved. The results apply to tempered Metadynamics with or without adaptive Gaussians or boundary corrections and whether the bias is stored approximately on a grid or exactly.
