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Free energy sampling methods allow studying the full dynamics of activated processes. Unfortunately, the affordable accuracy of the potential describing the energy and forces of the system is usually rather low. Here we introduce a new…

Chemical Physics · Physics 2019-04-04 GiovanniMaria Piccini , Michele Parrinello

This article describes nonequilibrium techniques for the calculation of free energies of solids using molecular dynamics (MD) simulations. These methods provide an alternative to standard equilibrium thermodynamic integration methods and…

Materials Science · Physics 2022-01-13 Rodrigo Freitas , Mark Asta , Maurice de Koning

Transition path sampling (TPS) is a powerful technique for investigating rare transitions, especially when the mechanism is unknown and one does not have access to the reaction coordinate. Straightforward application of TPS does not…

Chemical Physics · Physics 2019-07-11 Z. Faidon Brotzakis , Peter G. Bolhuis

We present a molecular simulation method to simultaneously find multiple transition pathways, and their associated free-energy profiles. The scheme extends path-metadynamics (PMD) [Phys. Rev. Lett. 109, 020601 (2012)] with multiple paths…

Statistical Mechanics · Physics 2025-06-23 Alberto Pérez de Alba Ortíz , Bernd Ensing

Free energy landscapes encode the kinetics, intermediates, and transition states that govern molecular processes and are thus a key target of single biomolecule research. Typical approaches to deriving optimal, error-minimizing,…

Biological Physics · Physics 2025-11-25 Oliver Cheng , Zosia Adamska , Michael P. Brenner , Megan C. Engel

The conformational free energy landscape of a system is a fundamental thermodynamic quantity of importance particularly in the study of soft matter and biological systems, in which the entropic contributions play a dominant role. While…

Biological Physics · Physics 2015-10-13 N. Ramakrishnan , Richard W. Tourdot , Ravi Radhakrishnan

Sampling the free energy surface, namely, the distribution of collective variables (CVs), is a crucial problem in statistical physics, as it underpins a better understanding of chemical reactions and conformational transitions. Traditional…

Machine Learning · Computer Science 2026-05-04 Zichen Liu , Tiejun Li

We propose a proof of convergence of an adaptive method used in molecular dynamics to compute free energy profiles. Mathematically, it amounts to studying the long-time behavior of a stochastic process which satisfies a non-linear…

Analysis of PDEs · Mathematics 2007-06-13 Tony Lelievre , Felix Otto , Mathias Rousset , Gabriel Stoltz

We introduce Adjoint Sampling, a highly scalable and efficient algorithm for learning diffusion processes that sample from unnormalized densities, or energy functions. It is the first on-policy approach that allows significantly more…

A free energy landscape estimation-method based on Bayesian inference is presented and used for comparing the efficiency of thermally enhanced sampling methods with respect to regular molecular dynamics, where the simulations are carried…

Biomolecules · Quantitative Biology 2017-04-04 Annie M. Westerlund , Tyler J. Harpole , Christian Blau , Lucie Delemotte

We present a method to explore the free energy landscapes of chemical reactions with post-transition-state bifurcations using an enhanced sampling method based on well-tempered metadynamics. Obviating the need for computationally expensive…

Chemical Physics · Physics 2023-04-18 Juno Nam , YounJoon Jung

Gradient-based methods are well-suited for derivative-free optimization (DFO), where finite-difference (FD) estimates are commonly used as gradient surrogates. Traditional stochastic approximation methods, such as Kiefer-Wolfowitz (KW) and…

Optimization and Control · Mathematics 2025-03-03 Guo Liang , Guangwu Liu , Kun Zhang

Diffusion models deliver state-of-the-art generative performance across diverse modalities but remain computationally expensive due to their inherently iterative sampling process. Existing training-free acceleration methods typically…

Machine Learning · Computer Science 2026-02-10 Cheng Jin , Zhenyu Xiao , Yuantao Gu

Because of their multimodality, mixture posterior distributions are difficult to sample with standard Markov chain Monte Carlo (MCMC) methods. We propose a strategy to enhance the sampling of MCMC in this context, using a biasing procedure…

Computation · Statistics 2011-04-19 Nicolas Chopin , Tony Lelievre , Gabriel Stoltz

The ability of widely used sampling methods, such as molecular dynamics or Monte Carlo, to explore complex free energy landscapes is severely hampered by the presence of kinetic bottlenecks. A large number of solutions have been proposed to…

Statistical Mechanics · Physics 2014-08-29 Omar Valsson , Michele Parrinello

Free energy perturbation (FEP) is frequently used to evaluate the free energy change of a biological process, e.g. the drug binding free energy or the ligand solvation free energy. Due to the sampling inefficiency, FEP is often employed…

Chemical Physics · Physics 2017-01-31 Ying-Chih Chiang , Frank Otto

The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated…

Computational Physics · Physics 2015-09-01 Alejandro Gil-Ley , Giovanni Bussi

When a system is driven out of equilibrium by a time-dependent protocol that modifies the Hamiltonian, it follows a nonequilibrium path. Samples of these paths can be used in nonequilibrium work theorems to estimate equilibrium quantities,…

Statistical Mechanics · Physics 2009-05-29 David D. L. Minh

We present convergence results for an adaptive algorithm to compute free energies, namely the adaptive biasing force (ABF) method. The free energy is the effective potential associated to a so-called reaction coordinate (RC). Computing free…

Analysis of PDEs · Mathematics 2010-05-20 Tony Lelievre , Kimiya Minoukadeh

We propose an adaptive biasing algorithm aimed at enhancing the sampling of multimodal measures by Langevin dynamics. The underlying idea consists in generalizing the standard adaptive biasing force method commonly used in conjunction with…

Analysis of PDEs · Mathematics 2010-08-23 Chris Chipot , Tony Lelièvre