{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:22:24Z","timestamp":1792653744290,"version":"4.5.0"},"reference-count":23,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"Intramural Research Program of the NIH","doi-asserted-by":"publisher","award":["ZIA EY000476-10"],"award-info":[{"award-number":["ZIA EY000476-10"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The inherited disorder oculocutaneous albinism type 1 (OCA1) is caused by mutations in the TYR gene encoding tyrosinase (Tyr), an enzyme essential to producing pigments throughout the human body. The intramelanosomal domain of Tyr consists of the cysteine-rich and tyrosinase catalytic subdomains, which are essential for enzymatic activity. In protein unfolding, the roles of these subdomains are not well established. Here, we performed six molecular dynamics simulations at room temperature for Tyr and OCA1-related mutant variants P406L and R402Q intramelanosomal domains. The proteins were simulated for 1 \u03bcs in water and urea to induce unfolding. In urea, we observed increases in surface area, decreases in intramolecular hydrogen bonding, and decreases in hydrophobic interactions, suggesting a \u2018molten globule\u2019 state for each protein. Between all conditions, the cysteine-rich subdomain remains stable, whereas the catalytic subdomain shows increased flexibility. This flexibility is intensified by the P406L mutation, while R402Q increases the catalytic domain\u2019s rigidity. The cysteine-rich subdomain is rigid, preventing the protein from unfolding, whereas the flexibility of the catalytic subdomain accommodates mutational changes that could inhibit activity. These findings match the conclusions from our experimental work suggesting the function alteration by the P406L mutation, and the potential role of R402Q as a polymorphism.<\/jats:p>","DOI":"10.3390\/ijms241713032","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:46:22Z","timestamp":1692665182000},"page":"13032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Evaluating the Cysteine-Rich and Catalytic Subdomains of Human Tyrosinase and OCA1-Related Mutants Using 1 \u03bcs Molecular Dynamics Simulation"],"prefix":"10.3390","volume":"24","author":[{"given":"Taariq","family":"Woods","sequence":"first","affiliation":[{"name":"National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7204-6572","authenticated-orcid":false,"given":"Yuri V.","family":"Sergeev","sequence":"additional","affiliation":[{"name":"National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1034\/j.1600-0749.2003.00045.x","article-title":"Oculocutaneous albinism type 1: The last 100 years","volume":"16","author":"Oetting","year":"2003","journal-title":"Pigment Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1007\/s00439-003-0998-1","article-title":"Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): Definition of the phenotype","volume":"113","author":"King","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yang, Q., Yi, S., Li, M., Xie, B., Luo, J., Wang, J., Rong, X., Zhang, Q., Qin, Z., and Hang, L. (2019). Genetic analyses of oculocutaneous albinism types 1 and 2 with four novel mutations. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0842-7"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8169","DOI":"10.1074\/jbc.275.11.8169","article-title":"Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control","volume":"275","author":"Negroiu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/chem.201704410","article-title":"Structure and Function of Human Tyrosinase and Tyrosinase-Related Proteins","volume":"24","author":"Lai","year":"2018","journal-title":"Chemistry"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Dolinska, M.B., Kovaleva, E., Backlund, P., Wingfield, P.T., Brooks, B.P., and Sergeev, Y.V. (2014). Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0084494"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/pcmr.12546","article-title":"Oculocutaneous albinism type 1: Link between mutations, tyrosinase conformational stability, and enzymatic activity","volume":"30","author":"Dolinska","year":"2017","journal-title":"Pigment Cell Melanoma R"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/0471721204.ch25","article-title":"Homology modeling","volume":"44","author":"Krieger","year":"2003","journal-title":"Methods Biochem. Anal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.15406\/japlr.2020.09.00356","article-title":"Functional in silico analysis of human tyrosinase and OCA1 associated mutations","volume":"9","author":"Patel","year":"2020","journal-title":"J. Anal. Pharm. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/j.1755-148X.2009.00636.x","article-title":"New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins","volume":"22","author":"Olivares","year":"2009","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.ijbiomac.2018.10.186","article-title":"Protein folding: Molecular dynamics simulations and in vitro studies for probing mechanism of urea- and guanidinium chloride-induced unfolding of horse cytochrome-c","volume":"122","author":"Khan","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15873","DOI":"10.1073\/pnas.1411798111","article-title":"The nature of protein folding pathways","volume":"111","author":"Englander","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","first-page":"1145","article-title":"Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: A new subtype of albinism classified as \u2018\u2018OCA3\u2019\u2019","volume":"58","author":"Boissy","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Uversky, V.N., and Finkelstein, A.V. (2019). Life in Phases: Intra- and Inter- Molecular Phase Transitions in Protein Solutions. Biomolecules, 9.","DOI":"10.3390\/biom9120842"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1006\/jmbi.1996.0172","article-title":"Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations","volume":"257","author":"Li","year":"1996","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-540-74686-7_1","article-title":"Introduction to molecular dynamics","volume":"739","author":"Schneider","year":"2008","journal-title":"Lect. Notes Phys."},{"key":"ref_17","first-page":"419","article-title":"Determination of proper time step for molecular dynamics simulation","volume":"21","author":"Choe","year":"2000","journal-title":"Bull. Kor. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/jcc.26524","article-title":"Algorithm to minimize MPI communications in the parallelized fast multipole method combined with molecular dynamics calculations","volume":"42","author":"Andoh","year":"2021","journal-title":"J. Comput. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/jcc.21209","article-title":"Accelerating molecular dynamic simulation on graphics processing units","volume":"30","author":"Friedrichs","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1006\/bbrc.1995.1221","article-title":"Identification of Molten Globule-Like State in an All Beta-Sheet Protein","volume":"207","author":"Kumar","year":"1995","journal-title":"Biochem. Bioph. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00128336","article-title":"Special Issue\u2014Mopac\u2014A Semiempirical Molecular-Orbital Program","volume":"4","author":"Stewart","year":"1990","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1021\/j100007a062","article-title":"Conductor-Like Screening Model for Real Solvents\u2014A New Approach to the Quantitative Calculation of Solvation Phenomena","volume":"99","author":"Klamt","year":"1995","journal-title":"J. Phys. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13032\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:39:06Z","timestamp":1760128746000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,22]]},"references-count":23,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713032"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713032","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,22]]}}}