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Metadynamics (MTD) is a very powerful technique to sample high-dimensional free energy landscapes, and due to its self-guiding property, the method has been successful in studying complex reactions and conformational changes. MTD sampling…

Computational Physics · Physics 2016-02-05 Shalini Awasthi , Venkat Kapil , Nisanth N. Nair

Methods that combine collective variable (CV) based enhanced sampling and global tempering approaches are used in speeding-up the conformational sampling and free energy calculation of large and soft systems with a plethora of energy…

Computational Physics · Physics 2021-09-01 Anji Babu Kapakayala , Nisanth N. Nair

A variety of enhanced sampling methods predict multidimensional free energy landscapes associated with biological and other molecular processes as a function of a few selected collective variables (CVs). The accuracy of these methods is…

Computational Physics · Physics 2024-04-09 Lukas Müllender , Andrea Rizzi , Michele Parrinello , Paolo Carloni , Davide Mandelli

A new approach for efficiently exploring the configuration space and computing the free energy of large atomic and molecular systems is proposed, motivated by an analogy with reinforcement learning. There are two major components in this…

Chemical Physics · Physics 2018-04-18 Linfeng Zhang , Han Wang , Weinan E

While recent advances in AI have transformed protein structure prediction, protein function is also strongly influenced by the thermodynamic and kinetic features encoded in its underlying free-energy surface. Here, we propose a…

Biological Physics · Physics 2026-04-29 Alexander Zhilkin , Muralika Medaparambath , Dan Mendels

The typically rugged nature of molecular free energy landscapes can frustrate efficient sampling of the thermodynamically relevant phase space due to the presence of high free energy barriers. Enhanced sampling techniques can improve phase…

Biomolecules · Quantitative Biology 2023-08-21 Nicholas S. M. Herringer , Siva Dasetty , Diya Gandhi , Junhee Lee , Andrew L. Ferguson

A microscopic theory of the free energy barriers and folding routes for minimally frustrated proteins is presented, greatly expanding on the presentation of the variational approach outlined previously [J. J. Portman, S. Takada, P. G.…

Soft Condensed Matter · Physics 2009-10-31 John J. Portman , Shoji Takada , Peter G. Wolynes

Describing the complex landscape of infinite-dimensional free energy is generally a challenging problem. This difficulty arises from the existence of numerous minimizers and, consequently, a vast number of saddle points. These factors make…

Soft Condensed Matter · Physics 2025-07-15 Keiichiro Kagawa , Takeshi Watanabe , Yasumasa Nishiura

One of the key limitations of Molecular Dynamics simulations is the computational intractability of sampling protein conformational landscapes associated with either large system size or long timescales. To overcome this bottleneck, we…

Biomolecules · Quantitative Biology 2018-07-09 Zahra Shamsi , Kevin J. Cheng , Diwakar Shukla

Enhanced sampling techniques have become an essential tool in computational chemistry and physics, where they are applied to sample activated processes that occur on a time scale that is inaccessible to conventional simulations. Despite…

Chemical Physics · Physics 2022-01-13 F. Giberti , G. A. Tribello , M. Ceriotti

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

Understanding protein conformational dynamics is essential for elucidating biological function but remains challenging due to the wide range of timescales and the complexity of collective motions. Enhanced sampling methods overcome…

Statistical Mechanics · Physics 2026-05-11 Souvik Mondal , Michael A. Sauer , Matthias Heyden

Metadynamics, a member of the `flat histogram' class of advanced sampling algorithms, has been widely used in molecular simulations to drive the exploration of states separated by high free energy barriers and promote comprehensive sampling…

Computational Physics · Physics 2021-09-13 Shanghui Huang , Michael J. Quevillon , Ernesto C. Cortés-Morales , Jonathan K. Whitmer

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

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 proposed a new technique to accelerate sampling methods for solving difficult optimization problems. Our method investigates the intrinsic connection between posterior distribution sampling and optimization with Langevin dynamics, and…

Machine Learning · Computer Science 2023-01-31 Junlong Lyu , Zhitang Chen , Wenlong Lyu , Jianye Hao

Molecular dynamics is a powerful tool for studying the thermodynamics and kinetics of complex molecular events. However, these simulations can rarely sample the required time scales in practice. Transition path sampling overcomes this…

Chemical Physics · Physics 2023-07-31 Gianmarco Lazzeri , Hendrik Jung , Peter G. Bolhuis , Roberto Covino

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

Metadynamics is a powerful computational tool to obtain the free energy landscape of complex systems. The Monte Carlo algorithm has proven useful to calculate thermodynamic quantities associated with simplified models of proteins, and thus…

Statistical Mechanics · Physics 2007-10-04 F. Marini , C. Camilloni , D. Provasi , R. A. Broglia , G. Tiana

Designing protein sequences that fold into a target 3-D structure, termed as the inverse folding problem, is central to protein engineering. However, it remains challenging due to the vast sequence space and the importance of local…

Quantitative Methods · Quantitative Biology 2026-03-17 Sazan Mahbub , Souvik Kundu , Eric P. Xing
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