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One reason that free energy difference calculations are notoriously difficult in molecular systems is due to insufficient conformational overlap, or similarity, between the two states or systems of interest. The degree of overlap is…

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

Sets of free energy differences are useful for finding the equilibria of chemical reactions, while absolute free energies have little physical meaning. However finding the relative free energy between two macrostates by subtraction of their…

Statistical Mechanics · Physics 2012-11-26 Joshua T. Berryman , Tanja Schilling

We present a new method to evaluate vibrational free energies of atomic systems without a priori specification of an interatomic potential. Our model-agnostic approach leverages descriptors, high-dimensional feature vectors of atomic…

Materials Science · Physics 2025-03-05 Thomas D Swinburne , Clovis Lapointe , Mihai-Cosmin Marinica

The nonequilibrium work fluctuation theorem provides the way for calculations of (equilibrium) free energy based on work measurements of nonequilibrium, finite-time processes and their reversed counterparts by applying Bennett's acceptance…

Statistical Mechanics · Physics 2010-04-26 Aljoscha M. Hahn , Holger Then

In this work, I propose a statistical mechanical framework, for the evaluation of the free energy in molecular systems, by "deleting" all the molecules in a "single" step. The approach can be considered as the statistical mechanics…

Statistical Mechanics · Physics 2011-08-16 Georgios C. Boulougouris

The absolute free energy -- or partition function, equivalently -- of a molecule can be estimated computationally using a suitable reference system. Here, we demonstrate a practical method for staging such calculations by growing a molecule…

Biological Physics · Physics 2009-01-31 Xin Zhang , Artem B. Mamonov , Daniel M. Zuckerman

Calculating relative free energies is a topic of substantial interest and has many applications including solvation and binding free energies, which are used in computational drug discovery. However, there remain the challenges of accuracy,…

Chemical Physics · Physics 2016-09-28 Asaf Farhi , Bipin Singh

The accurate estimation of free energy differences between two states is a long-standing challenge in molecular simulations. Traditional approaches generally rely on sampling multiple intermediate states to ensure sufficient overlap in…

Statistical Mechanics · Physics 2026-03-17 Maximilian Schebek , Jiajun He , Emil Hoffmann , Yuanqi Du , Frank Noé , Jutta Rogal

The Gibbs free energy is the fundamental thermodynamic potential underlying the relative stability of different states of matter under constant-pressure conditions. However, computing this quantity from atomic-scale simulations is far from…

Materials Science · Physics 2018-02-14 Bingqing Cheng , Michele Ceriotti

We develop an efficient sampling and free energy calculation technique within the adaptive biasing potential (ABP) framework. By mollifying the density of states we obtain an approximate free energy and an adaptive bias potential that is…

Statistical Mechanics · Physics 2010-01-29 Bradley M. Dickson , Frederic Legoll , Tony Lelievre , Gabriel Stoltz , Paul Fleurat-Lessard

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

We present a method to obtain numerically accurate values of configurational free energies of semiflexible macromolecular systems, based on the technique of thermodynamic integration combined with normal-mode analysis of a reference system…

Biomolecules · Quantitative Biology 2018-10-17 Stefan M. Giovan , Robert G. Scharein , Andreas Hanke , Stephen D. Levene

Estimating the free energy in molecular simulation requires, implicitly or explicitly, counting how many times the system is observed in a finite region. If the simulation is biased by an external potential, the weight of the configurations…

Chemical Physics · Physics 2021-12-22 Matteo Carli , Alessandro Laio

We present a novel method for the calculation of the energy density of states D(E) for systems described by classical statistical mechanics. The method builds on an extension of a recently proposed strategy that allows the free energy…

Statistical Mechanics · Physics 2009-11-10 Cristian Micheletti , Alessandro Laio , Michele Parrinello

Taking advantage of the advances in generative deep learning, particularly normalizing flow, a framework, called Boltzmann Generator, has recently been proposed for the purpose of generating equilibrium atomic configurations from the…

Statistical Mechanics · Physics 2022-07-27 Rasool Ahmad , Wei Cai

Calculating free energy differences is a topic of substantial interest and has many applications including molecular docking and hydration, solvation, and binding free energies which is used in computational drug discovery. However, in…

Chemical Physics · Physics 2013-10-16 Asaf Farhi

A powerful and well-established tool for free-energy estimation is Bennett's acceptance ratio method. Central properties of this estimator, which employs samples of work values of a forward and its time reversed process, are known: for…

Statistical Mechanics · Physics 2009-09-16 Aljoscha Maria Hahn , Holger Then

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

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

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
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