{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:37:57Z","timestamp":1781109477018,"version":"3.54.1"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T00:00:00Z","timestamp":1672099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["PHY-2019745"],"award-info":[{"award-number":["PHY-2019745"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["PHY-2210291"],"award-info":[{"award-number":["PHY-2210291"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["Grant C-1792"],"award-info":[{"award-number":["Grant C-1792"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"DST | Science and Engineering Research Board","doi-asserted-by":"publisher","award":["CRG\/2020\/000756"],"award-info":[{"award-number":["CRG\/2020\/000756"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:p>Kinesin motor proteins perform several essential cellular functions powered by the adenosine triphosphate (ATP) hydrolysis reaction. Several single-point mutations in the kinesin motor protein KIF5A have been implicated to hereditary spastic paraplegia disease (HSP), a lethal neurodegenerative disease in humans. In earlier studies, we have shown that a series of HSP-related mutations can impair the kinesin\u2019s long-distance displacement or processivity by modulating the order\u2013disorder transition of the linker connecting the heads to the coiled coil. On the other hand, the reduction of kinesin\u2019s ATP hydrolysis reaction rate by a distal asparagine-to-serine mutation is also known to cause HSP disease. However, the molecular mechanism of the ATP hydrolysis reaction in kinesin by this distal mutation is still not fully understood. Using classical molecular dynamics simulations combined with quantum mechanics\/molecular mechanics calculations, the pre-organization geometry required for optimal hydrolysis in kinesin motor bound to \u03b1\/\u03b2-tubulin is determined. This optimal geometry has only a single salt-bridge (of the possible two) between Arg203-Glu236, putting a reactive water molecule at a perfect position for hydrolysis. Such geometry is also needed to create the appropriate configuration for proton translocation during ATP hydrolysis. The distal asparagine-to-serine mutation is found to disrupt this optimal geometry. Therefore, the current study along with our previous one demonstrates how two different effects on kinesin dynamics (processivity and ATP hydrolysis), caused by a different set of genotypes, can give rise to the same phenotype leading to HSP disease.<\/jats:p>","DOI":"10.1073\/pnas.2215170120","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T16:25:01Z","timestamp":1672158301000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-8985","authenticated-orcid":false,"given":"Rabindra Nath","family":"Manna","sequence":"first","affiliation":[{"name":"School of Chemical Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-0388","authenticated-orcid":false,"given":"Jos\u00e9 N.","family":"Onuchic","sequence":"additional","affiliation":[{"name":"Center for Theoretical Biological Physics, Rice University, Houston, TX 77005"},{"name":"Department of Physics and Astronomy, Rice University, Houston, TX 77005"},{"name":"Department of Chemistry, Rice University, Houston, TX 77005"},{"name":"Department of Biosciences, Rice University, Houston, TX 77005"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7684-1963","authenticated-orcid":false,"given":"Biman","family":"Jana","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/35036069"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2774"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn0856"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2004.08.011"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.2.284"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180353"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn014"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810622115"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023659118"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.10.037"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1913650116"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706014114"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908192106"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b11708"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.0c10004"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1039\/C6CP04496D"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1800054115"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1039\/C6CP01364C"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP02194A"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja211027m"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.6b03365"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b03193"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja401540g"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701727104"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00016"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2624"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21816"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540040211"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.4236\/jbpc.2013.42008"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp003020w"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.448118"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.100.020603"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpc.2009.05.011"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00214a001"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.438955"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-987X(200009)21:12<1088::AID-JCC5>3.0.CO;2-8"},{"key":"e_1_3_4_42_2","unstructured":"M. J. Frisch Gaussian 09 Revision A.02 (Gaussian Inc. Wallingford CT 2016)."},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b13655"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1660"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.8b03201"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21759"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.3382344"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1039\/b508541a"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1039\/b515623h"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2215170120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:46:37Z","timestamp":1695285997000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2215170120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1,3]]}},"alternative-id":["10.1073\/pnas.2215170120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2215170120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]},"assertion":[{"value":"2022-09-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2215170120"}}