{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:30:51Z","timestamp":1783488651527,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ANID FONDECYT Regular","award":["1221308"],"award-info":[{"award-number":["1221308"]}]},{"name":"ANID FONDECYT Regular","award":["SA77210065"],"award-info":[{"award-number":["SA77210065"]}]},{"name":"Subvenci\u00f3n a la Instalaci\u00f3n a la Academia","award":["1221308"],"award-info":[{"award-number":["1221308"]}]},{"name":"Subvenci\u00f3n a la Instalaci\u00f3n a la Academia","award":["SA77210065"],"award-info":[{"award-number":["SA77210065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phospholipase C\u03b6 (PLC\u03b6), a sperm-specific enzyme, plays a critical role in mammalian fertilization. Mutations in PLC\u03b6 have been linked to male infertility, as they impair its ability to trigger calcium (Ca2+) oscillations necessary for egg activation and embryo development. During fertilization, PLC\u03b6 is introduced into the egg, where it hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate and diacylglycerol, leading to Ca2+ release from the endoplasmic reticulum. Human infertility-associated mutations include H233L, H398P, and R553P, which disrupt PLC\u03b6 function. To elucidate the molecular consequences of the mutations, we employed full-atom molecular dynamics simulations to analyze structural perturbations and their impact on PIP2 and Ca2+ binding. Our results reveal that H233L and H398P mutations significantly reduce interactions with PIP2, disrupting hydrogen bonding and salt bridge formation, leading to misalignment of the substrate. Additionally, these mutations destabilize Ca2+ binding by altering its positioning within the active site. In contrast, the R553P mutation primarily affects intramolecular stability and enzyme dynamics without impairing substrate or ion binding. Free energy calculations indicate an increased affinity for PIP2 in H233L and H398P mutants, leading to an aberrant substrate positioning and compromised hydrolysis. These structural insights help explain the egg activation failure and infertility of patients carrying these mutations.<\/jats:p>","DOI":"10.3390\/ijms26104706","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T10:06:52Z","timestamp":1747217212000},"page":"4706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structural Implications of H233L and H398P Mutations in Phospholipase C\u03b6: A Full-Atom Molecular Dynamics Study on Infertility-Associated Dysfunctions"],"prefix":"10.3390","volume":"26","author":[{"given":"Fernando","family":"Hinostroza","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n de Estudios Avanzados del Maule (CIEAM), Vicerrector\u00eda de Investigaci\u00f3n y Postgrado, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"},{"name":"Centro de Investigaci\u00f3n en Neuropsicolog\u00eda y Neurociencias Cognitivas (CINPSI Neurocog), Facultad de Ciencias de la Salud, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"},{"name":"Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"},{"name":"Centro para la Investigaci\u00f3n Traslacional en Neurofarmacolog\u00eda, Universidad de Valpara\u00edso, Valpara\u00edso 2340000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9563-3515","authenticated-orcid":false,"given":"Sof\u00eda","family":"Albornoz-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Escuela de Ingenier\u00eda en Biotecnolog\u00eda, Facultad de Ciencias Agrarias y Forestales, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebasti\u00e1n","family":"Vergara","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3871-0261","authenticated-orcid":false,"given":"Gabriela","family":"Urra","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Araya-Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology (CBIB), Universidad Andr\u00e9s Bello, Santiago 8370146, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael A.","family":"Fissore","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-3575","authenticated-orcid":false,"given":"Fernando Danilo","family":"Gonz\u00e1lez-Nilo","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology (CBIB), Universidad Andr\u00e9s Bello, Santiago 8370146, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-2305","authenticated-orcid":false,"given":"Daniel","family":"Bustos","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioinform\u00e1tica y Qu\u00edmica Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2311-7239","authenticated-orcid":false,"given":"Ingrid","family":"Carvacho","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Cat\u00f3lica del Maule, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1093\/humrep\/der336","article-title":"Loss of Activity Mutations in Phospholipase C Zeta (PLC\u03b6) Abolishes Calcium Oscillatory Ability of Human Recombinant Protein in Mouse Oocytes","volume":"26","author":"Kashir","year":"2011","journal-title":"Hum. 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