{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T16:46:19Z","timestamp":1772383579799,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010009","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000}}],"reference-count":91,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31872723"],"award-info":[{"award-number":["31872723"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in\n                    <jats:italic>ALPL<\/jats:italic>\n                    , the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of\n                    <jats:italic>ALPL<\/jats:italic>\n                    mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the\n                    <jats:italic>ALPL<\/jats:italic>\n                    mutations on protein dynamics and function. Statistical analysis of molecular features computed for the\n                    <jats:italic>ALPL<\/jats:italic>\n                    mutations showed a significant difference between the control, mild and severe HPP phenotypes. Molecular dynamics simulations coupled with protein structure network analysis were employed to analyze the effect of single-residue variation on conformational dynamics of TNSALP dimers, and the developed machine learning model suggested that the topological network parameters could serve as a robust indicator of severe mutations. The results indicated that the severity of disease-associated mutations is often linked with mutation-induced modulation of allosteric communications in the protein. This study suggested that\n                    <jats:italic>ALPL<\/jats:italic>\n                    mutations associated with mild and more severe HPPs can exert markedly distinct effects on the protein stability and long-range network communications. By linking the disease phenotypes with dynamic and allosteric molecular signatures, the proposed integrative computational approach enabled to characterize and quantify the allosteric effects of\n                    <jats:italic>ALPL<\/jats:italic>\n                    mutations and role of allostery in the pathogenesis of HPPs.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010009","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T13:41:34Z","timestamp":1648042894000},"page":"e1010009","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5262-2475","authenticated-orcid":true,"given":"Fei","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-6907","authenticated-orcid":true,"given":"Ziyun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-7864","authenticated-orcid":true,"given":"Xingyu","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3292-3921","authenticated-orcid":true,"given":"Mi","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gennady","family":"Verkhivker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8754-1541","authenticated-orcid":true,"given":"Guang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"issue":"6","key":"pcbi.1010009.ref001","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1001\/archpedi.1948.02030020840003","article-title":"Hypophosphatasia; a new developmental anomaly","volume":"75","author":"JC Rathbun","year":"1948","journal-title":"American journal of diseases of children"},{"key":"pcbi.1010009.ref002","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.metabol.2017.08.013","article-title":"Hypophosphatasia.","volume":"82","author":"E Mornet","year":"2018","journal-title":"Metabolism: clinical and experimental"},{"issue":"3","key":"pcbi.1010009.ref003","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.job.2019.07.003","article-title":"Molecular and cellular basis of hypophosphatasia","volume":"61","author":"K Komaru","year":"2019","journal-title":"Journal of oral biosciences"},{"key":"pcbi.1010009.ref004","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.bone.2015.02.022","article-title":"Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients","volume":"75","author":"MP Whyte","year":"2015","journal-title":"Bone"},{"key":"pcbi.1010009.ref005","doi-asserted-by":"crossref","first-page":"144855","DOI":"10.1016\/j.gene.2020.144855","article-title":"Alkaline phosphatase: Structure, expression and its function in bone mineralization","volume":"754","author":"S. 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