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Free energy calculations based on atomistic Hamiltonians provide microscopic insight into the thermodynamic driving forces of biophysical or condensed matter systems. Many approaches use intermediate Hamiltonians interpolating between the…

Computational Physics · Physics 2021-12-08 Martin Reinhardt , Helmut Grubmüller

Free energy difference calculations based on atomistic simulations generally improve in accuracy when sampling from a sequence of intermediate equilibrium thermodynamic states that bridge the configuration space between two states of…

Computational Physics · Physics 2020-10-21 Martin Reinhardt , Helmut Grubmüller

Ensuring a satisfactory statistical convergence of anharmonic thermodynamic properties requires sampling of many atomic configurations, however the methods to obtain those necessarily produce correlated samples, thereby reducing the…

Statistical Mechanics · Physics 2022-06-07 Erki Metsanurk

The multistate Bennett Acceptance Ratio is provably the lowest variance unbiased estimator of both free energies and ensemble averages, and has a number of important advantages over previous methods, such as WHAM. Despite its advantages,…

Statistical Mechanics · Physics 2017-12-20 Michael R. Shirts

The multistate Bennett acceptance ratio (MBAR) method is a prevalent approach for computing free energies of thermodynamic states. In this work, we introduce BayesMBAR, a Bayesian generalization of the MBAR method. By integrating…

Chemical Physics · Physics 2024-02-16 Xinqiang Ding

We consider the problem of estimating the energy of a quantum state preparation for a given Hamiltonian in Pauli decomposition. For various quantum algorithms, in particular in the context of quantum chemistry, it is crucial to have energy…

Quantum Physics · Physics 2025-08-20 Alexander Gresch , Uğur Tepe , Martin Kliesch

We present a new estimator for computing free energy differences and thermodynamic expectations as well as their uncertainties from samples obtained from multiple equilibrium states via either simulation or experiment. The estimator, which…

Computational Physics · Physics 2011-12-06 Michael R. Shirts , John D. Chodera

The dynamics of molecules are governed by rare event transitions between long-lived (metastable) states. To explore these transitions efficiently, many enhanced sampling protocols have been introduced that involve using simulations with…

Chemical Physics · Physics 2022-09-30 Maaike M. Galama , Hao Wu , Andreas Krämer , Mohsen Sadeghi , Frank Noé

We present a detailed comparison of computational efficiency and precision for several free energy difference ($\Delta F$) methods. The analysis includes both equilibrium and non-equilibrium approaches, and distinguishes between…

Biological Physics · Physics 2009-11-11 F. Marty Ytreberg , Robert H. Swendsen , Daniel M. Zuckerman

Obtaining the free energies of condensed phase chemical reactions remains computationally prohibitive for high-level quantum mechanical methods. We introduce a hierarchical machine learning framework that bridges this gap by distilling…

Chemical Physics · Physics 2026-03-19 Chenghan Li , Garnet Kin-Lic Chan

Inspired by the recent development on calculating the free energy change via a relaxation process [Nat. Phys. 14, 842 (2018)], we investigate the role of heat released in an irreversible relaxation following a large perturbation. Utilizing…

Accurate calculations of solvation free energies remain a central challenge in molecular simulations, often requiring extensive sampling and numerous alchemical intermediates to ensure sufficient overlap between phase-space distributions of…

Statistical Mechanics · Physics 2026-04-02 Maximilian Schebek , Nikolas M. Froböse , Bettina G. Keller , Jutta Rogal

We develop a quantum algorithm for estimating the free energy as well as the total Gibbs state of interacting quantum Coulomb gases and molecular systems in dimensions $d \in \{2,3\}$ at finite temperature. These systems lie beyond the…

Quantum Physics · Physics 2026-04-17 Simon Becker , Cambyse Rouzé , Robert Salzmann

Estimating free energy differences, an important problem in computational drug discovery and in a wide range of other application areas, commonly involves a computationally intensive process of sampling a family of high-dimensional…

In QM/MM indirect free energy simulation, QM/MM corrections can be obtained from integration of partial derivatives of alchemical Hamiltonians or from perturbation-based estimators including free energy perturbation (FEP) and acceptance…

Chemical Physics · Physics 2018-10-05 Xiaohui Wang , Zhaoxi Sun

An energy-biased method to evaluate ensemble averages requiring test-particle insertion is presented. The method is based on biasing the sampling within the subdomains of the test-particle configurational space with energies smaller than a…

Chemical Physics · Physics 2009-11-11 R. Delgado-Buscalioni , G. De Fabritiis , P. V. Coveney

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

Free energy of crystal phases is commonly evaluated by thermodynamic integration (TDI) along a reversible path that involves an external potential. A persistent problem in this method is that a significant hysteresis is observed due to…

Materials Science · Physics 2010-02-27 Pankaj A. Apte

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

A novel overlap histogramming method based on Dual-Topology Hamiltonian-Replica-Exchange simulation technique is presented to efficiently calculate relative free energy difference in rough energy landscape, in which multiple conformers…

Chemical Physics · Physics 2013-06-24 Donghong Min , Hongzhi Li , Guohui Li , Ryan Bitter-Putzer , Wei Yang
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