{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T09:10:25Z","timestamp":1784020225323,"version":"3.55.0"},"reference-count":110,"publisher":"AIP Publishing","issue":"10","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["200021-175944"],"award-info":[{"award-number":["200021-175944"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["200021-178762"],"award-info":[{"award-number":["200021-178762"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,9,14]]},"abstract":"<jats:p>Replica-exchange enveloping distribution sampling (RE-EDS) is a pathway-independent multistate free-energy method currently implemented in the GROMOS software package for molecular dynamics (MD) simulations. It has a high intrinsic sampling efficiency as the interactions between the unperturbed particles have to be calculated only once for multiple end-states. As a result, RE-EDS is an attractive method for the calculation of relative solvation and binding free energies. An essential requirement for reaching this high efficiency is the separability of the nonbonded interactions into solute\u2013solute, solute\u2013environment, and environment\u2013environment contributions. Such a partitioning is trivial when using a Coulomb term with a reaction-field (RF) correction to model the electrostatic interactions but not when using lattice-sum schemes. To avoid cutoff artifacts, the RF correction is typically used in combination with a charge-group-based cutoff, which is not supported by most small-molecule force fields as well as other MD engines. To address this issue, we investigate the combination of RE-EDS simulations with a recently introduced RF scheme including a shifting function that enables the rigorous calculation of RF electrostatics with atom-based cutoffs. The resulting approach is validated by calculating solvation free energies with the generalized AMBER force field in water and chloroform using both the GROMOS software package and a proof-of-concept implementation in OpenMM.<\/jats:p>","DOI":"10.1063\/5.0107935","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T18:35:15Z","timestamp":1660242915000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Leveraging the sampling efficiency of RE-EDS in OpenMM using a shifted reaction-field with an atom-based cutoff"],"prefix":"10.1063","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-651X","authenticated-orcid":false,"given":"Salom\u00e9 R.","family":"Rieder","sequence":"first","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0945-8304","authenticated-orcid":false,"given":"Benjamin","family":"Ries","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6518-681X","authenticated-orcid":false,"given":"Al\u017ebeta","family":"Kubincov\u00e1","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6982-1569","authenticated-orcid":false,"given":"Candide","family":"Champion","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9755-260X","authenticated-orcid":false,"given":"Emilia P.","family":"Barros","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9420-7998","authenticated-orcid":false,"given":"Philippe H.","family":"H\u00fcnenberger","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-4031","authenticated-orcid":false,"given":"Sereina","family":"Riniker","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry, ETH Z\u00fcrich , Vladimir-Prelog-Weg 2, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"2023081006150680500_c1","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1002\/minf.201000051","article-title":"Rigorous free energy calculations in structure-based drug design","volume":"29","year":"2010","journal-title":"Mol. Inform."},{"key":"2023081006150680500_c2","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s10822-011-9517-y","article-title":"The future of molecular dynamics simulations in drug discovery","volume":"26","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2023081006150680500_c3","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of molecular dynamics and related methods in drug discovery","volume":"59","year":"2016","journal-title":"J. Med. Chem."},{"key":"2023081006150680500_c4","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1021\/acs.jcim.7b00564","article-title":"Relative binding free energy calculations in drug discovery: Recent advances and practical considerations","volume":"57","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c5","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1021\/acs.jmedchem.7b00681","article-title":"Free energy methods in drug design: Prospects of \u2018alchemical perturbation\u2019 in medicinal chemistry","volume":"61","year":"2018","journal-title":"J. Med. Chem."},{"key":"2023081006150680500_c6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/acs.jcim.9b01174","article-title":"Novel directions in free energy methods and applications","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c7","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1021\/acs.jcim.0c00116","article-title":"Rigorous free energy simulations in virtual screening","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c8","doi-asserted-by":"publisher","first-page":"5595","DOI":"10.1021\/acs.jcim.0c00613","article-title":"Alchemical binding free energy calculations in AMBER20: Advances and best practices for drug discovery","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c9","doi-asserted-by":"publisher","first-page":"5308","DOI":"10.1021\/acs.jcim.0c00547","article-title":"Evolution of alchemical free energy methods in drug discovery","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c10","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1063\/1.1749657","article-title":"Statistical mechanics of fluid mixtures","volume":"3","year":"1935","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c11","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1063\/1.1740409","article-title":"High-temperature equation of state by a perturbation method. I. Nonpolar gases","volume":"22","year":"1954","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c12","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/0021-9991(76)90078-4","article-title":"Efficient estimation of free energy differences from Monte Carlo data","volume":"22","year":"1976","journal-title":"J. Comput. Phys."},{"key":"2023081006150680500_c13","doi-asserted-by":"publisher","first-page":"124105","DOI":"10.1063\/1.2978177","article-title":"Statistically optimal analysis of samples from multiple equilibrium states","volume":"129","year":"2008","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c14","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1021\/ct200444f","article-title":"Multisite \u03bb dynamics for simulated structure\u2013activity relationship studies","volume":"7","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c15","doi-asserted-by":"publisher","first-page":"7895","DOI":"10.1021\/acs.jctc.0c00830","article-title":"Automated, accurate, and scalable relative protein\u2013ligand binding free-energy calculations using \u03bb dynamics","volume":"16","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c16","doi-asserted-by":"publisher","first-page":"6799","DOI":"10.1021\/acs.jctc.1c00833","article-title":"BLaDE: A basic lambda dynamics engine for GPU-accelerated molecular dynamics free energy calculations","volume":"17","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c17","doi-asserted-by":"publisher","first-page":"184110","DOI":"10.1063\/1.2730508","article-title":"Enveloping distribution sampling: A method to calculate free energy differences from a single simulation","volume":"126","year":"2007","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c18","doi-asserted-by":"publisher","first-page":"174112","DOI":"10.1063\/1.2913050","article-title":"Multiple free energies from a single simulation: Extending enveloping distribution sampling to nonoverlapping phase-space distributions","volume":"128","year":"2008","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c19","doi-asserted-by":"publisher","first-page":"154114","DOI":"10.1063\/1.4964781","article-title":"Replica exchange enveloping distribution sampling (RE-EDS): A robust method to estimate multiple free-energy differences from a single simulation","volume":"145","year":"2016","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c20","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1021\/acs.jctc.7b00286","article-title":"Efficient round-trip time optimization for replica-exchange enveloping distribution sampling (RE-EDS)","volume":"13","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c21","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s10822-021-00436-z","article-title":"Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure","volume":"36","year":"2021","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2023081006150680500_c22","doi-asserted-by":"publisher","first-page":"3043","DOI":"10.1021\/acs.jcim.2c00383","article-title":"Replica-exchange enveloping distribution sampling using generalized AMBER force-field topologies: Application to relative hydration free-energy calculations for large sets of molecules","volume":"62","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c23","doi-asserted-by":"publisher","first-page":"5030","DOI":"10.1021\/acs.jpcb.8b02725","article-title":"Accelerated enveloping distribution sampling: Enabling sampling of multiple end states while preserving local energy minima","volume":"122","year":"2018","journal-title":"J. Phys. Chem. B"},{"key":"2023081006150680500_c24","doi-asserted-by":"publisher","first-page":"5395","DOI":"10.1021\/acs.jcim.0c00456","article-title":"Toward automated free energy calculation with accelerated enveloping distribution sampling (A-EDS)","volume":"60","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c25","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.cpc.2011.12.014","article-title":"Architecture, implementation and parallelization of the GROMOS software for biomolecular simulation","volume":"183","year":"2012","journal-title":"Comput. Phys. Commun."},{"key":"2023081006150680500_c26","doi-asserted-by":"publisher","first-page":"024105","DOI":"10.1063\/1.3604534","article-title":"Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors","volume":"135","year":"2011","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c27","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/s0009-2614(97)01198-6","article-title":"Parallel tempering algorithm for conformational studies of biological molecules","volume":"281","year":"1997","journal-title":"Chem. Phys. Lett."},{"key":"2023081006150680500_c28","doi-asserted-by":"publisher","first-page":"6042","DOI":"10.1063\/1.1308516","article-title":"Multidimensional replica-exchange method for free-energy calculations","volume":"113","year":"2000","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c29","doi-asserted-by":"publisher","first-page":"2738","DOI":"10.1021\/ct500175m","article-title":"Constant pH molecular dynamics in explicit solvent with enveloping distribution sampling and Hamiltonian exchange","volume":"10","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c30","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/biomet\/57.1.97","article-title":"Monte Carlo sampling methods using Markov chains and their applications","volume":"57","year":"1970","journal-title":"Biometrika"},{"key":"2023081006150680500_c31","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s10822-022-00445-6","article-title":"RestraintMaker: A graph-based approach to select distance restraints in free-energy calculations with dual topology","volume":"36","year":"2022","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2023081006150680500_c32","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1126\/science.220.4599.787","article-title":"Van der waals picture of liquids, solids, and phase transformations","volume":"220","year":"1983","journal-title":"Science"},{"key":"2023081006150680500_c33","doi-asserted-by":"publisher","first-page":"5156","DOI":"10.1063\/1.452636","article-title":"The influence of long-range force truncation on the thermodynamics of aqueous ionic solutions","volume":"86","year":"1987","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c34","doi-asserted-by":"publisher","first-page":"5856","DOI":"10.1021\/bi00140a022","article-title":"Cutoff size does strongly influence molecular dynamics results on solvated polypeptides","volume":"31","year":"1992","journal-title":"Biochemistry"},{"key":"2023081006150680500_c35","doi-asserted-by":"publisher","first-page":"6342","DOI":"10.1063\/1.474295","article-title":"Effect of electrostatic boundary conditions and system size on the interfacial properties of water and aqueous solutions","volume":"107","year":"1997","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c36","doi-asserted-by":"publisher","first-page":"6117","DOI":"10.1063\/1.476022","article-title":"Alternative schemes for the inclusion of a reaction-field correction into molecular dynamics simulations: Influence on the simulated energetic, structural, and dielectric properties of liquid water","volume":"108","year":"1998","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c37","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.1021\/jp807421a","article-title":"Molecular dynamics simulations of a reversibly folding \u03b2-heptapeptide in methanol: Influence of the treatment of long-range electrostatic interactions","volume":"113","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"2023081006150680500_c38","doi-asserted-by":"publisher","first-page":"5451","DOI":"10.1063\/1.469273","article-title":"A generalized reaction field method for molecular dynamics simulations","volume":"102","year":"1995","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c39","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/andp.19213690304","article-title":"Die Berechnung optischer und elektrostatischer Gitterpotentiale","volume":"369","year":"1921","journal-title":"Ann. Phys."},{"key":"2023081006150680500_c40","volume-title":"Computer Simulation Using Particles","year":"2021"},{"key":"2023081006150680500_c41","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u22c5log(N) method for Ewald sums in large systems","volume":"98","year":"1993","journal-title":"SoftwareX"},{"key":"2023081006150680500_c42","doi-asserted-by":"publisher","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","year":"1995","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c43","doi-asserted-by":"publisher","first-page":"26419","DOI":"10.1039\/d0cp03835k","article-title":"Reaction-field electrostatics in molecular dynamics simulations: Development of a conservative scheme compatible with an atomic cutoff","volume":"22","year":"2020","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081006150680500_c44","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1090\/s0025-5718-1965-0178586-1","article-title":"An algorithm for the machine calculation of complex Fourier series","volume":"19","year":"1965","journal-title":"Math. Comput."},{"key":"2023081006150680500_c45","article-title":"Lattice-sum methods for computing electrostatic interactions in molecular simulations","volume-title":"Simulation and Theory of Electrostatic Interactions in Solution: Computational Chemistry, Biophysics, and Aqueous Solution","author":"Hummer","year":"1999"},{"key":"2023081006150680500_c46","doi-asserted-by":"publisher","first-page":"4501","DOI":"10.1021\/jp806724u","article-title":"A blind challenge for computational solvation free energies: Introduction and overview","volume":"113","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"2023081006150680500_c47","doi-asserted-by":"publisher","first-page":"7556","DOI":"10.1021\/acs.jctc.0c00688","article-title":"Evaluating classical force fields against experimental cross-solvation free energies","volume":"16","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c48","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1109\/mcse.2010.27","article-title":"OpenMM: A hardware-independent framework for molecular simulations","volume":"12","year":"2010","journal-title":"Comput. Sci. Eng."},{"key":"2023081006150680500_c49","doi-asserted-by":"publisher","first-page":"e1005659","DOI":"10.1371\/journal.pcbi.1005659","article-title":"OpenMM 7: Rapid development of high performance algorithms for molecular dynamics","volume":"13","year":"2017","journal-title":"PLoS Comput. Biol."},{"key":"2023081006150680500_c50","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s10822-014-9747-x","article-title":"FreeSolv: A database of experimental and calculated hydration free energies, with input files","volume":"28","year":"2014","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2023081006150680500_c51","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1021\/acs.jced.7b00104","article-title":"Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database","volume":"62","year":"2017","journal-title":"J. Chem. Eng. Data"},{"key":"2023081006150680500_c52"},{"key":"2023081006150680500_c53","first-page":"1","volume-title":"Biomolecular Simulation: The GROMOS96 Manual and User Guide","year":"1996"},{"key":"2023081006150680500_c54","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1021\/acs.jcim.8b00042","article-title":"Fixed-charge atomistic force fields for molecular dynamics simulations in the condensed phase: An overview","volume":"58","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"2023081006150680500_c55","unstructured":"See http:\/\/gromos.net for \u201cThe GROMOS software for (bio)molecular simulation, volume 2\u201d (2021); accessed: 2022\/05\/05."},{"key":"2023081006150680500_c56","doi-asserted-by":"publisher","first-page":"9129","DOI":"10.1063\/1.1614202","article-title":"Influence of cut-off truncation and artificial periodicity of electrostatic interactions in molecular simulations of solvated ions: A continuum electrostatics study","volume":"119","year":"2003","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c57","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1002\/jcc.20303","article-title":"The GROMOS software for biomolecular simulation: GROMOS05","volume":"26","year":"2005","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c58","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1021\/ct100610v","article-title":"On the calculation of the dielectric permittivity and relaxation of molecular models in the liquid phase","volume":"7","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c59","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1002\/jcc.21954","article-title":"New functionalities in the GROMOS biomolecular simulation software","volume":"33","year":"2012","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c60","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general Amber force field","volume":"25","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c61","volume-title":"AMBER Reference Manual","year":"2016"},{"key":"2023081006150680500_c62","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/jcc.540050311","article-title":"On searching neighbors in computer simulations of macromolecular systems","volume":"5","year":"1984","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c63","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1002\/jcc.20090","article-title":"A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6","volume":"25","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c64","doi-asserted-by":"publisher","first-page":"4026","DOI":"10.1021\/ct200196m","article-title":"An automated force field topology builder (ATB) and repository: Version 1.0","volume":"7","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c65","doi-asserted-by":"publisher","first-page":"3825","DOI":"10.1021\/acs.jctc.6b00187","article-title":"A GROMOS-compatible force field for small organic molecules in the condensed phase: The 2016H66 parameter set","volume":"12","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c66","doi-asserted-by":"publisher","first-page":"7525","DOI":"10.1021\/acs.jctc.0c00683","article-title":"Systematic optimization of a fragment-based force field against experimental pure-liquid properties considering large compound families: Application to saturated haloalkanes","volume":"16","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c67","doi-asserted-by":"publisher","first-page":"17774","DOI":"10.1039\/d1cp02001c","article-title":"Systematic optimization of a fragment-based force field against experimental pure-liquid properties considering large compound families: Application to oxygen and nitrogen compounds","volume":"23","year":"2021","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2023081006150680500_c68","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1089\/cmb.2012.0239","article-title":"Charge group partitioning in biomolecular simulation","volume":"20","year":"2013","journal-title":"J. Comput. Biol."},{"key":"2023081006150680500_c69","doi-asserted-by":"publisher","first-page":"3336","DOI":"10.1063\/1.1676585","article-title":"Molecular dynamics study of liquid water","volume":"55","year":"1971","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c70","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1080\/00268977900101751","article-title":"The computer simulation of polar liquids","volume":"38","year":"1979","journal-title":"Mol. Phys."},{"key":"2023081006150680500_c71","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/ct0502256","article-title":"The origin of layer structure artifacts in simulations of liquid water","volume":"2","year":"2006","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c72","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1080\/08927020701783566","article-title":"Explicit-solvent molecular dynamics simulations of a DNA tetradecanucleotide duplex: Lattice-sum versus reaction-field electrostatics","volume":"34","year":"2008","journal-title":"Mol. Simul."},{"key":"2023081006150680500_c73","doi-asserted-by":"publisher","first-page":"2883","DOI":"10.1007\/s00894-011-0975-x","article-title":"Effect of atom- and group-based truncations on biomolecules simulated with reaction-field electrostatics","volume":"17","year":"2011","journal-title":"J. Mol. Model."},{"key":"2023081006150680500_c74","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1-2","year":"2015","journal-title":"SoftwareX"},{"key":"2023081006150680500_c75"},{"key":"2023081006150680500_c76","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An overview of the Amber biomolecular simulation package","volume":"3","year":"2013","journal-title":"Wiley Interdiscip. Rev.: Comput. Mol. Sci."},{"key":"2023081006150680500_c77","doi-asserted-by":"publisher","first-page":"9811","DOI":"10.1063\/1.1476316","article-title":"Derivation of an improved simple point charge model for liquid water: SPC\/A and SPC\/L","volume":"116","year":"2002","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c78","doi-asserted-by":"publisher","first-page":"184103","DOI":"10.1063\/1.4826261","article-title":"Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: An accurate correction scheme for electrostatic finite-size effects","volume":"139","year":"2013","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c79","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/jcc.23490","article-title":"Net charge changes in the calculation of relative ligand-binding free energies via classical atomistic molecular dynamics simulations","volume":"35","year":"2014","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c80","doi-asserted-by":"publisher","first-page":"7721","DOI":"10.1021\/acs.jctc.0c00719","article-title":"Charge-changing perturbations and path sampling via classical molecular dynamic simulations of simple guest-host systems","volume":"16","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c81","unstructured":"J.\u2008Swails, C.\u2008Hernandez, D. L.\u2008Mobley, H.\u2008Nguyen, L.-P.\u2008Wang, and P.\u2008Janowski, ParmEd, https:\/\/github.com\/ParmEd\/ParmEd, 2010; accessed: 2022\/05\/05."},{"key":"2023081006150680500_c82","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1109\/mcse.2011.37","article-title":"The NumPy array: A structure for efficient numerical computation","volume":"13","year":"2011","journal-title":"Comput. Sci. Eng."},{"key":"2023081006150680500_c83","doi-asserted-by":"publisher","first-page":"56","DOI":"10.25080\/majora-92bf1922-00a","article-title":"Data structures for statistical computing in Python","volume":"445","year":"2010","journal-title":"Proc. 9th Python Sci. Conf."},{"key":"2023081006150680500_c84","doi-asserted-by":"publisher","first-page":"4532","DOI":"10.1063\/1.460608","article-title":"The overlooked bond-stretching contribution in free energy perturbation calculations","volume":"94","year":"1991","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c85","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1126\/science.2727695","article-title":"Hidden thermodynamics of mutant proteins: A molecular dynamics analysis","volume":"244","year":"1989","journal-title":"Science"},{"key":"2023081006150680500_c86"},{"key":"2023081006150680500_c87"},{"key":"2023081006150680500_c88","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","article-title":"Automatic atom type and bond type perception in molecular mechanical calculations","volume":"25","year":"2006","journal-title":"J. Mol. Graph. Model."},{"key":"2023081006150680500_c89","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/(sici)1096-987x(20000130)21:2&lt;132::aid-jcc5&gt;3.0.co;2-p","article-title":"Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method","volume":"21","year":"2000","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c90","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1002\/jcc.10128","article-title":"Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation","volume":"23","year":"2002","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c91","doi-asserted-by":"publisher","first-page":"3379","DOI":"10.1021\/ct2003622","article-title":"The GROMOS++ software for the analysis of biomolecular simulation trajectories","volume":"7","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c92"},{"key":"2023081006150680500_c93","unstructured":"W. F.\u2008van Gunsteren, gromos.net, http:\/\/www.gromos.net\/, 2021; accessed: 2022\/01\/06."},{"key":"2023081006150680500_c94","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","year":"1983","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c95","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1080\/00268979400101331","article-title":"A molecular dynamics simulation study of chloroform","volume":"83","year":"1994","journal-title":"Mol. Phys."},{"key":"2023081006150680500_c96","volume-title":"Handbook of Chemistry and Physics","year":"2007-2008","edition":"88th ed."},{"key":"2023081006150680500_c97","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","year":"1984","journal-title":"J. Chem. Phys."},{"key":"2023081006150680500_c98","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.cplett.2003.12.039","article-title":"Molecular dynamics simulations of water and biomolecules with a Monte Carlo constant pressure algorithm","volume":"384","year":"2004","journal-title":"Chem. Phys. Lett."},{"key":"2023081006150680500_c99","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","year":"1977","journal-title":"J. Comput. Phys."},{"key":"2023081006150680500_c100","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1002\/jcc.540130805","article-title":"Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models","volume":"13","year":"1992","journal-title":"J. Comput. Chem."},{"key":"2023081006150680500_c101","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1021\/ct900463w","article-title":"Constant constraint matrix approximation: A robust, parallelizable constraint method for molecular simulations","volume":"6","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"2023081006150680500_c102","unstructured":"M. R.\u2008Shirts, \u201cReweighting from the mixture distribution as a better way to describe the multistate Bennett acceptance ratio,\u201d arXiv:1704.00891 (2017)."},{"key":"2023081006150680500_c103","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1142\/1893","article-title":"GROMACS: A parallel computer for molecular dynamics simulations","volume-title":"Physics Computing 92","author":"DeGroot","year":"1993"},{"key":"2023081006150680500_c104"},{"key":"2023081006150680500_c105","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1109\/mcse.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"2023081006150680500_c106"},{"key":"2023081006150680500_c107","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: Fundamental algorithms for scientific computing in Python","volume":"17","year":"2020","journal-title":"Nat. Methods"},{"key":"2023081006150680500_c108","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: Statistical data visualization","volume":"6","year":"2021","journal-title":"J. Open Source Software"},{"key":"2023081006150680500_c109","doi-asserted-by":"publisher","first-page":"72","DOI":"10.2307\/1412159","article-title":"The proof and measurement of association between two things","volume":"15","year":"1904","journal-title":"Am. J. Psychol."},{"key":"2023081006150680500_c110","doi-asserted-by":"crossref","unstructured":"D. F.\u2008Hahn, C. I.\u2008Bayly, H. E.\u2008Bruce Macdonald, J. D.\u2008Chodera, A. S. J. S.\u2008Mey, D. L.\u2008Mobley, L.\u2008Perez Benito, C. E. M.\u2008Schindler, G.\u2008Tresadern, and G. L.\u2008Warren, \u201cBest practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks,\u201d arXiv:2105.06222 (2021).","DOI":"10.33011\/livecoms.4.1.1497"}],"container-title":["The Journal of Chemical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0107935\/16550622\/104117_1_online.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0107935\/16550622\/104117_1_online.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0107935\/16550622\/104117_1_online.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T20:20:39Z","timestamp":1748377239000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/jcp\/article\/157\/10\/104117\/2841792\/Leveraging-the-sampling-efficiency-of-RE-EDS-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":110,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,9,14]]}},"URL":"https:\/\/doi.org\/10.1063\/5.0107935","relation":{},"ISSN":["0021-9606","1089-7690"],"issn-type":[{"value":"0021-9606","type":"print"},{"value":"1089-7690","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9,14]]},"published":{"date-parts":[[2022,9,13]]},"article-number":"104117"}}