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However, they typically involve relatively short (&amp;lt;10 ns) simulations, meaning that the initial coordinates and, more generally, the setup of the system have a significant effect on the obtained free energy values. To remedy this, we recently developed a fully adaptive version of the simulated tempering algorithm (FAST) and applied it in the context of sampling. In this work, we extend FAST to AFE calculations with and without enhanced sampling of a particular degree of freedom of interest (FAST\/MBAR). We show that enhanced sampling significantly increases the mobility of the targeted degree of freedom at the cost of reduced sampling efficiency over \u03bb space. On the other hand, the free energy calculations without explicit targeting of certain degrees of freedom retain initial-coordinate bias over longer time scales. Despite this, both protocols readily explore nanosecond-time-scale events, such as torsional rotation, due to the single-trajectory nature of FAST, making them less sensitive to the system preparation. It is shown that the robust automated nature of FAST\/MBAR makes it a competitive alternative to conventional AFE methods.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c00963","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:15:06Z","timestamp":1784819706000},"page":"7993-8012","source":"Crossref","is-referenced-by-count":0,"title":["Fully Automatable\nRelative Binding Free Energy Calculations\nwith Enhanced Sampling Using FAST\/MBAR"],"prefix":"10.1021","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6794-1679","authenticated-orcid":true,"given":"Miroslav","family":"Suruzhon","sequence":"first","affiliation":[{"name":"University of Southampton , , , ,","place":["Highfield, Southampton, U.K., SO17 1BJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9745-0777","authenticated-orcid":true,"given":"Justina","family":"Ratkeviciute","sequence":"additional","affiliation":[{"name":"University of Southampton , , , ,","place":["Highfield, Southampton, U.K., SO17 1BJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Abdel-Maksoud","sequence":"additional","affiliation":[{"name":"University of Southampton , , , ,","place":["Highfield, Southampton, U.K., SO17 1BJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cavalleri","sequence":"additional","affiliation":[{"name":"University of Southampton , , , ,","place":["Highfield, Southampton, U.K., SO17 1BJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9172-1203","authenticated-orcid":true,"given":"Michael S.","family":"Bodnarchuk","sequence":"additional","affiliation":[{"name":"AstraZeneca , , ,","place":["Cambridge, U.K., CB4 0WG"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-2050","authenticated-orcid":true,"given":"Antonella","family":"Ciancetta","sequence":"additional","affiliation":[{"name":"BioCity , , Pennyfoot St , ,","place":["Nottingham, U.K., NG1 1GR"]},{"name":"University of Ferrara , , Via Fossato di Mortara 17\/19 , ,","place":["Ferrara, Italy, 44121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8207-5457","authenticated-orcid":true,"given":"Ian D.","family":"Wall","sequence":"additional","affiliation":[{"name":"GSK Medicines Research Centre , Gunnels Wood Road , ,","place":["Stevenage, U.K., SG1 2NY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2639-2746","authenticated-orcid":true,"given":"Jonathan W.","family":"Essex","sequence":"additional","affiliation":[{"name":"University of Southampton , , , ,","place":["Highfield, Southampton, U.K., SO17 1BJ"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"2026081111101198800_cit1","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1021\/acs.jcim.7b00564","article-title":"Relative Binding Free Energy Calculations\nin Drug Discovery: Recent Advances and Practical Considerations","volume":"57","author":"Cournia","year":"2017","journal-title":"J. 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