{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:37:27Z","timestamp":1793230647536,"version":"4.5.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"15","license":[{"start":{"date-parts":[[2017,11,7]],"date-time":"2017-11-07T00:00:00Z","timestamp":1510012800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM056207"],"award-info":[{"award-number":["GM056207"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human DNA polymerase \u03b7 (Pol \u03b7) plays a vital role in protection against skin cancer caused by damage from ultraviolet light. This enzyme rescues stalled replication forks at cyclobutane thymine\u2013thymine dimers (TTDs) by inserting nucleotides opposite these DNA lesions. Residue R61 is conserved in the Pol \u03b7 enzymes across species, but the corresponding residue, as well as its neighbor S62, is different in other Y-family polymerases, Pol \u03b9 and Pol \u03ba. Herein, R61 and S62 are mutated to their Pol \u03b9 and Pol \u03ba counterparts. Relative binding free energies of dATP to mutant Pol \u03b7\u2022DNA complexes with and without a TTD were calculated using thermodynamic integration. The binding free energies of dATP to the Pol \u03b7\u2022DNA complex with and without a TTD are more similar for all of these mutants than for wild-type Pol \u03b7, suggesting that these mutations decrease the ability of this enzyme to distinguish between a TTD lesion and undamaged DNA. Molecular dynamics simulations of the mutant systems provide insights into the molecular level basis for the changes in relative binding free energies. The simulations identified differences in hydrogen-bonding, cation\u2212\u03c0, and \u03c0\u2013\u03c0 interactions of the side chains with the dATP and the TTD or thymine\u2013thymine (TT) motif. The simulations also revealed that R61 and Q38 act as a clamp to position the dATP and the TTD or TT and that the mutations impact the balance among the interactions related to this clamp. Overall, these calculations suggest that R61 and S62 play key roles in the specificity and effectiveness of Pol \u03b7 for bypassing TTD lesions during DNA replication. Understanding the basis for this specificity is important for designing drugs aimed at cancer treatment.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6b09973","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T10:37:45Z","timestamp":1478515065000},"page":"3667-3675","source":"Crossref","is-referenced-by-count":7,"title":["Effects of Active Site Mutations on Specificity of\nNucleobase Binding in Human DNA Polymerase \u03b7"],"prefix":"10.1021","volume":"121","author":[{"given":"Melek N.","family":"Ucisik","sequence":"first","affiliation":[{"name":"University of Illinois at Urbana-Champaign , , 600 South Mathews Avenue , , ,","place":["Urbana, Illinois, United States, 61801-3364"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-6995","authenticated-orcid":true,"given":"Sharon","family":"Hammes-Schiffer","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana-Champaign , , 600 South Mathews Avenue , , ,","place":["Urbana, Illinois, United States, 61801-3364"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2016,11,7]]},"reference":[{"key":"2026090115180297300_cit1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nrc2998","article-title":"DNA polymerases\nand cancer","volume":"11","author":"Lange","year":"2011","journal-title":"Nat. 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