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Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host\u2013guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68<jats:inline-formula><jats:alternatives><jats:tex-math>$${\\text{kcal}}\/{\\text{mol}}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:mrow><mml:mtext>kcal<\/mml:mtext><mml:mo>\/<\/mml:mo><mml:mtext>mol<\/mml:mtext><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of<jats:inline-formula><jats:alternatives><jats:tex-math>$$2.65$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:mrow><mml:mn>2.65<\/mml:mn><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>and<jats:inline-formula><jats:alternatives><jats:tex-math>$$1.72 {\\text{kcal}}\/{\\text{mol}}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\"><mml:mrow><mml:mn>1.72<\/mml:mn><mml:mtext>kcal<\/mml:mtext><mml:mo>\/<\/mml:mo><mml:mtext>mol<\/mml:mtext><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>, respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.<\/jats:p>","DOI":"10.1007\/s10822-021-00385-7","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T20:21:57Z","timestamp":1620073317000},"page":"667-677","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A replica exchange umbrella sampling (REUS) approach to predict host\u2013guest binding free energies in SAMPL8 challenge"],"prefix":"10.1007","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2184-4494","authenticated-orcid":false,"given":"Mahdi","family":"Ghorbani","sequence":"first","affiliation":[]},{"given":"Phillip S.","family":"Hudson","sequence":"additional","affiliation":[]},{"given":"Michael R.","family":"Jones","sequence":"additional","affiliation":[]},{"given":"F\u00e9lix","family":"Aviat","sequence":"additional","affiliation":[]},{"given":"Rub\u00e9n","family":"Meana-Pa\u00f1eda","sequence":"additional","affiliation":[]},{"given":"Jeffery B.","family":"Klauda","sequence":"additional","affiliation":[]},{"given":"Bernard R.","family":"Brooks","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"issue":"9","key":"385_CR1","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","volume":"59","author":"M De Vivo","year":"2016","unstructured":"De Vivo M, Masetti M, Bottegoni G, Cavalli A (2016) J Med Chem 59(9):4035","journal-title":"J Med Chem"},{"issue":"15","key":"385_CR2","doi-asserted-by":"publisher","first-page":"2644","DOI":"10.1002\/1521-3773(20020802)41:15<2644::AID-ANIE2644>3.0.CO;2-O","volume":"41","author":"H Gohlke","year":"2002","unstructured":"Gohlke H, Klebe G (2002) Angew Chem Int Ed 41(15):2644","journal-title":"Angew Chem Int Ed"},{"issue":"6","key":"385_CR3","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1021\/ar800236t","volume":"42","author":"WL Jorgensen","year":"2009","unstructured":"Jorgensen WL (2009) Acc Chem Res 42(6):724","journal-title":"Acc Chem Res"},{"issue":"45","key":"385_CR4","doi-asserted-by":"publisher","first-page":"15959","DOI":"10.1021\/ja055013x","volume":"127","author":"S Liu","year":"2005","unstructured":"Liu S, Ruspic C, Mukhopadhyay P, Chakrabarti S, Zavalij PY, Isaacs L (2005) J Am Chem Soc 127(45):15959","journal-title":"J Am Chem Soc"},{"issue":"32","key":"385_CR5","first-page":"9897","volume":"20","author":"J V\u00e1zquez","year":"2014","unstructured":"V\u00e1zquez J, Rem\u00f3n P, Dsouza RN, Lazar AI, Arteaga JF, Nau WM, Pischel U (2014) Chemistry A 20(32):9897","journal-title":"Chemistry A"},{"issue":"3\u20134","key":"385_CR6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s10847-008-9464-y","volume":"62","author":"P Rajgariah","year":"2008","unstructured":"Rajgariah P, Urbach AR (2008) J Incl Phenom Macrocycl Chem 62(3\u20134):251","journal-title":"J Incl Phenom Macrocycl Chem"},{"key":"385_CR7","volume-title":"Chemistry","author":"S Murkli","year":"2020","unstructured":"Murkli S, Klemm J, Brockett AT, Shuster M, Briken V, Roesch MR, Isaacs L (2020) Chemistry. 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