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Sampling from discrete distributions with multiple modes and energy barriers is fundamental to machine learning and computational physics. Recent discrete neural samplers like MDNS suffer from mode collapse and fail to sample high-energy…

The sampling problem lies at the heart of atomistic simulations and over the years many different enhanced sampling methods have been suggested towards its solution. These methods are often grouped into two broad families. On the one hand…

Computational Physics · Physics 2020-11-25 Michele Invernizzi , Pablo Miguel Piaggi , Michele Parrinello

Machine learning methods provide a general framework for automatically finding and representing the essential characteristics of simulation data. This task is particularly crucial in enhanced sampling simulations. There we seek a few…

Chemical Physics · Physics 2021-07-07 Jakub Rydzewski , Omar Valsson

The free energy landscapes of several fundamental processes are characterized by high barriers separating long-lived metastable states. In order to explore these type of landscapes enhanced sampling methods are used. While many such methods…

Chemical Physics · Physics 2019-04-12 Jayashrita Debnath , Michele Invernizzi , Michele Parrinello

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…

Computational Physics · Physics 2020-07-15 Davide Mandelli , Barak Hirshberg , Michele Parrinello

We show how thermodynamic properties of molecular models can be computed over a large, multidimensional parameter space by combining multistate reweighting analysis with a linear basis function approach. This approach reduces the…

Chemical Physics · Physics 2016-05-18 Levi N. Naden , Michael R. Shirts

To address the time-scale limitations in molecular dynamics (MD) simulations, numerous enhanced sampling methods have been developed to expedite the exploration of complex free energy landscapes. A commonly employed approach accelerates the…

Computational Physics · Physics 2025-06-24 Zhijun Pan , Maodong Li , Dechin Chen , Yi Isaac Yang

We propose two metadynamics (MetaD)-based methodologies for efficiently mapping free energy surfaces (FESs) of multiple interacting carriers diffusing in crystalline solids. Our approaches circumvent the challenges of high-dimensional…

Materials Science · Physics 2026-05-25 Shunya Yamada , Kazuaki Toyoura

Enhanced sampling methods are indispensable in computational physics and chemistry, where atomistic simulations cannot exhaustively sample the high-dimensional configuration space of dynamical systems due to the sampling problem. A class of…

Chemical Physics · Physics 2024-04-04 Jakub Rydzewski , Ming Chen , Tushar K. Ghosh , Omar Valsson

We demonstrate how a prior assumption of smoothness can be used to enhance the reconstruction of free energy profiles from multiple umbrella sampling simulations using the Bayesian Gaussian process regression approach. The method we derive…

Statistical Mechanics · Physics 2014-07-25 Noam Bernstein , Thomas Stecher , Gábor Csányi

We review a selection of methods for performing enhanced sampling in molecular dynamics simulations. We consider methods based on collective variable biasing and on tempering, and offer both historical and contemporary perspectives. In…

Statistical Mechanics · Physics 2014-01-03 Cameron Abrams , Giovanni Bussi

Free energy profiles serve as a fundamental bridge between microscopic atomic fluctuations and macroscopic thermodynamic observables. Estimating the free energy profile along a reaction coordinate, referred to as the potential of mean force…

Biased sampling in molecular dynamics simulations overcomes timescale limitations and delivers free-energy landscapes, essential to understand complex atomistic phenomena. However, when applied across diverse systems and processes, biasing…

Statistical Mechanics · Physics 2026-01-14 Eline K. Kempkes , Alberto Pérez de Alba Ortíz

Well-Tempered Metadynamics (WTmetaD) is an efficient method to enhance the reconstruction of the free-energy surface of proteins. WTmetaD guarantees a faster convergence in the long time limit in comparison with the standard metadynamics.…

Biological Physics · Physics 2015-06-12 Francois Sicard , Patrick Senet

Enhanced sampling methods are pivotal for exploring rare events in molecular dynamics (MD), yet face challenges in high-dimensional collective variable (CV) spaces where exhaustive sampling becomes computationally prohibitive. While…

Computational Physics · Physics 2026-01-15 Zhijun Pan , Maodong Li , Dechin Chen , Yi Isaac Yang

Computing accurate reaction rates is a central challenge in computational chemistry and biology because of the high cost of free energy estimation with unbiased molecular dynamics. In this work, a data-driven machine learning algorithm is…

Computational Physics · Physics 2020-12-08 Lixin Sun , Jonathan Vandermause , Simon Batzner , Yu Xie , David Clark , Wei Chen , Boris Kozinsky

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

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

The universal mathematical form of machine-learning potentials (MLPs) shifts the core of development of interatomic potentials to collecting proper training data. Ideally, the training set should encompass diverse local atomic environments…

Computational Physics · Physics 2021-08-17 Dongsun Yoo , Jisu Jung , Wonseok Jeong , Seungwu Han

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