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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

We introduce a method for elucidating and modifying the functionality of systems dominated by rare events that relies on the automated tuning of their underlying free energy surface. The proposed approach seeks to construct collective…

Computational Physics · Physics 2021-08-31 Dan Mendels , Juan J. de Pablo

Mini-proteins and peptides manifest dynamic conformational fluctuation and involve mutual interconversion among metastable states. A robust mapping of the conformational landscape underlying mini-proteins and peptides often requires…

Chemical Physics · Physics 2021-09-29 Satyabrata Bandyopadhyay , Jagannath Mondal

This work examines the conformational ensemble involved in $\beta$-hairpin folding by means of advanced molecular dynamics simulations and dimensionality reduction. A fully atomistic description of the protein and the surrounding solvent…

Chemical Physics · Physics 2023-06-16 Albert Ardevol , Gareth A. Tribello , Michele Ceriotti , Michele Parrinello

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

Free energy biasing methods have proven to be powerful tools to accelerate the simulation of important conformational changes of molecules by modifying the sampling measure. However, most of these methods rely on the prior knowledge of…

Biological Physics · Physics 2021-10-20 Zineb Belkacemi , Paraskevi Gkeka , Tony Lelièvre , Gabriel Stoltz

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

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

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

Many processes of scientific importance are characterized by time scales that extend far beyond the reach of standard simulation techniques. To circumvent this impediment a plethora of enhanced sampling methods has been developed. One…

Computational Physics · Physics 2018-12-05 Dan Mendels , Giovannimaria Piccini , Z. Faidon Brotzakis , Yi I. Yang , Michele Parrinello

In molecular dynamics simulations, rare events, such as protein folding, are typically studied using enhanced sampling techniques, most of which are based on the definition of a collective variable (CV) along which acceleration occurs.…

Chemical Physics · Physics 2024-07-22 Soojung Yang , Juno Nam , Johannes C. B. Dietschreit , Rafael Gómez-Bombarelli

Molecular adsorption at organic/metal interfaces depends on a range of mechanisms: covalent bonds, charge transfer, Pauli repulsion and van der Waals (vdW) interactions shape the potential energy surface (PES), making it key to…

Computational Physics · Physics 2020-09-29 Lukas Hörmann , Andreas Jeindl , Oliver T. Hofmann

Conformational sampling of biomolecules using molecular dynamics simulations often produces large amount of high dimensional data that makes it difficult to interpret using conventional analysis techniques. Dimensionality reduction methods…

Biomolecules · Quantitative Biology 2021-12-08 Mahdi Ghorbani , Samarjeet Prasad , Jeffery B. Klauda , Bernard R. Brooks

Many enhanced sampling methods, such as Umbrella Sampling, Metadynamics or Variationally Enhanced Sampling, rely on the identification of appropriate collective variables. For proteins, even small ones, finding appropriate collective…

Chemical Physics · Physics 2017-09-15 Ferruccio Palazzesi , Omar Valsson , Michele Parrinello

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 protein's function depends critically on its conformational ensemble, a collection of energy weighted structures whose balance depends on temperature and environment. Though recent deep learning (DL) methods have substantially advanced…

Biomolecules · Quantitative Biology 2026-01-09 Myeongsang Lee , Lauren L. Porter

We present a method for determining the free energy dependence on a selected number of collective variables using an adaptive bias. The formalism provides a unified description which has metadynamics and canonical sampling as limiting…

Statistical Mechanics · Physics 2008-03-31 Alessandro Barducci , Giovanni Bussi , Michele Parrinello

Enhanced sampling techniques such as umbrella sampling and metadynamics are now routinely used to provide information on how the thermodynamic potential, or free energy, depends on a small number of collective variables. The free energy…

Computational Physics · Physics 2018-08-31 Ilaria Gimondi , Gareth A. Tribello , Matteo Salvalaglio

Controlling polymorphism in molecular crystals is crucial in the pharmaceutical, dye, and pesticide industries. However, its theoretical description is extremely challenging, due to the associated long timescales ($ > 1 \, \mu s$). We…

Chemical Physics · Physics 2023-02-09 Oren Elishav , Roy Podgaetsky , Olga Meikler , Barak Hirshberg

The conformation space of a 20-residue antiparallel $\beta$-sheet peptide, sampled by molecular dynamics simulations, is mapped to a network. Conformations are nodes of the network, and the transitions between them are links. The…

Biomolecules · Quantitative Biology 2007-05-23 Francesco Rao , Amedeo Caflisch
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