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Unfortunately, high levels of accuracy often require computationally expensive QM\/MM Hamiltonians. Fortuitously, the cost of employing QM\/MM approaches in rigorous free energy simulation can be reduced through the use of the so-called \u201cindirect\u201d approach to QM\/MM free energies, in which the need for QM\/MM simulations is avoided via a QM\/MM \u201ccorrection\u201d at the classical endpoints of interest. Herein, we focus on the computation of QM\/MM binding free energies in the context of the SAMPL8 Drugs of Abuse host\u2013guest challenge. Of the 5 QM\/MM correction coupled with force-matching submissions, PM6-D3H4\/MM ranked submission proved the best overall QM\/MM entry, with an RMSE from experimental results of 2.43 kcal\/mol (best in ranked submissions), a Pearson\u2019s correlation of 0.78 (second-best in ranked submissions), and a Kendall <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\tau$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u03c4<\/mml:mi>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> correlation of 0.52 (best in ranked submissions).<\/jats:p>","DOI":"10.1007\/s10822-022-00443-8","type":"journal-article","created":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T02:02:25Z","timestamp":1653184945000},"page":"263-277","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Obtaining QM\/MM binding free energies in the SAMPL8 drugs of abuse challenge: indirect approaches"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1856-1135","authenticated-orcid":false,"given":"Phillip S.","family":"Hudson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e9lix","family":"Aviat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Meana-Pa\u00f1eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Warrensford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin C.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samarjeet","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. 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