{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:57:35Z","timestamp":1767963455212,"version":"3.49.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T00:00:00Z","timestamp":1456876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Plasmepsin V belongs to the plasmepsin family of aspartic proteases. PlmV is unique compared to other plasmepsins, as this membrane bound aspartic protease resides in the endoplasmic reticulum and is responsible for the cleavage of PEXEL tagged proteins destined for export outside of the host red blood cell. Plasmepsin V is highly conserved throughout the Plasmodium species, and is essential to the survival of the parasite. Recently, two potent inhibitors of Plmv have been identified, WEHI-916 and WEHI-842. Of these inhibitors, WEHI-842 has a higher binding affinity for P. vivax PlmV, and a crystal structure of PlmV in complex with WEHI-842 has recently been resolved (4ZL4). The structure of PlmV is unique compared to other plasmepsins; it is stabilised internally by seven disulfide bonds, a NAP1 insert\/fold is associated with the movement of the flap covering the active site and a highly conserved helix-turn-helix is situated towards the C-terminus. Flap motion and dynamics play an important role in enzyme selectivity and function. To better understand the impact of ligand binding on the flap dynamics, molecular dynamic simulations and post-dynamic analysis were employed in the present study on PlmV in complex with WEHI-842. Previously defined parameters, which accurately accounted for the opening and closing of the active site, were used to assess the conformational changes induced in the absence and presence of WEHI-842. From the simulations it can be seen that inhibitor binding significantly reduces the flexibility and mobility of not only the flap and flexible loop but areas outside of the active site. Ligand binding leads to the formation of a more stable compact structure. This being said, there is a possibility of reducing the flexibility even further with potentially more lethal effects on the plasmodium parasite. We believe that results presented herein would assist researchers in the discovery of potent PlmV inhibitors as potential antimalarial therapies.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/c6mb00077k","type":"journal-article","created":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T07:09:44Z","timestamp":1456902584000},"page":"1457-1467","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The binding landscape of plasmepsin V and the implications for flap dynamics"],"prefix":"10.1093","volume":"12","author":[{"given":"McGillewie","family":"L.","sequence":"first","affiliation":[{"name":"Molecular Modelling & Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal a , Westville, Durban 4001 South Africa \u00a0 soliman@ukzn.ac.za \u00a0 +27 031 260 7792 \u00a0 +27 031 260 7413"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud E","family":"Soliman","sequence":"additional","affiliation":[{"name":"Molecular Modelling & Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal a , Westville, Durban 4001 South Africa \u00a0 soliman@ukzn.ac.za \u00a0 +27 031 260 7792 \u00a0 +27 031 260 7413"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,3,2]]},"reference":[{"key":"2026010815212390400_cit1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nature09107","article-title":"Thousands of chemical starting points for antimalarial lead identification","volume":"465","author":"Gamo","year":"2010","journal-title":"Nature"},{"key":"2026010815212390400_cit2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/00062752-200203000-00010","article-title":"Hydrolysis of erythrocyte proteins by proteases of malaria parasites","volume":"9","author":"Rosenthal","year":"2002","journal-title":"Curr. Opin. Hematol."},{"key":"2026010815212390400_cit3","author":"WHO \u2013 World Health Organization, 2015"},{"key":"2026010815212390400_cit4","doi-asserted-by":"crossref","first-page":"7644","DOI":"10.1021\/jm500797g","article-title":"Transition state mimetics of the Plasmodium export element are potent inhibitors of Plasmepsin V from P. falciparum and P. vivax","volume":"57","author":"Sleebs","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026010815212390400_cit5","doi-asserted-by":"crossref","first-page":"7644","DOI":"10.1021\/jm500797g","article-title":"Transition State Mimetics of the Plasmodium Export Element Are Potent Inhibitors of Plasmepsin V from P. falciparum and P. vivax","author":"Sleebs","year":"2014","journal-title":"J. Med. 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Chem."},{"key":"2026010815212390400_cit25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.molbiopara.2015.05.004","article-title":"Plasmodium falciparum Plasmepsin V (PfPMV): Insights into recombinant expression, substrate specificity and active site structure","volume":"201","author":"Boonyalai","year":"2015","journal-title":"Mol. Biochem. Parasitol."},{"key":"2026010815212390400_cit26","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"2026010815212390400_cit27","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the Amber ff99SB protein force field","volume":"78","author":"Lindorff-Larsen","year":"2010","journal-title":"Proteins"},{"key":"2026010815212390400_cit28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: an advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminf."},{"key":"2026010815212390400_cit29","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2026010815212390400_cit30","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"2026010815212390400_cit31","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"2026010815212390400_cit32","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1103\/PhysRevA.33.3628","article-title":"Molecular dynamics simulation for polymers in the presence of a heat bath","volume":"33","author":"Grest","year":"1986","journal-title":"Phys. Rev. A: At., Mol., Opt. Phys."},{"key":"2026010815212390400_cit33","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"2026010815212390400_cit34","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"2026010815212390400_cit35","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.cpc.2012.09.022","article-title":"SPFP: Speed without compromise\u2014A mixed precision model for GPU accelerated molecular dynamics simulations","volume":"184","author":"Le Grand","year":"2013","journal-title":"Comput. Phys. Commun."},{"key":"2026010815212390400_cit36"},{"key":"2026010815212390400_cit37","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1039\/C4MB00631C","article-title":"Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics","volume":"11","author":"Karubiu","year":"2015","journal-title":"Mol. BioSyst."},{"key":"2026010815212390400_cit38","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/prot.340170408","article-title":"Essential dynamics of proteins","volume":"17","author":"Amadei","year":"1993","journal-title":"Proteins: Struct., Funct., Genet."},{"key":"2026010815212390400_cit39","doi-asserted-by":"crossref","first-page":"e1003176","DOI":"10.1371\/journal.pcbi.1003176","article-title":"From Principal Component to Direct Coupling Analysis of Coevolution in Proteins: Low-Eigenvalue Modes are Needed for Structure Prediction","volume":"9","author":"Cocco","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"2026010815212390400_cit40","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0006-3495(97)78147-5","article-title":"Molecular dynamics study of time-correlated protein domain motions and molecular flexibility: cytochrome P450BM-3","volume":"73","author":"Arnold","year":"1997","journal-title":"Biophys. J."},{"key":"2026010815212390400_cit41","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1021\/ja00007a054","article-title":"Investigation of domain structure in proteins via molecular dynamics simulation: application to HIV-1 protease dimer","volume":"113","author":"Swaminathan","year":"1991","journal-title":"J. Am. Chem. Soc."},{"key":"2026010815212390400_cit42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1472-6807-11-31","article-title":"Dynamical Basis for Drug Resistance of HIV-1 Protease","volume":"11","author":"Mao","year":"2011","journal-title":"BMC Struct. Biol."},{"key":"2026010815212390400_cit43","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1529\/biophysj.106.102780","article-title":"Dynamics of firefly luciferase inhibition by general anesthetics: Gaussian and anisotropic network analyses","volume":"93","author":"Szarecka","year":"2007","journal-title":"Biophys. J."},{"key":"2026010815212390400_cit44","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1134\/S0026893308040195","article-title":"Radius of gyration as an indicator of protein structure compactness","volume":"42","author":"Lobanov","year":"2008","journal-title":"Mol. Biol."},{"key":"2026010815212390400_cit45","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/0022-2836(84)90231-6","article-title":"Solvent accessible surface area and excluded volume in proteins","volume":"178","author":"Richmond","year":"1984","journal-title":"J. Mol. Biol."},{"key":"2026010815212390400_cit46","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nature08726","article-title":"Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte","volume":"463","author":"Russo","year":"2010","journal-title":"Nature"}],"container-title":["Molecular BioSystems"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article-pdf\/12\/5\/1457\/65476365\/c6mb00077k.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article-pdf\/12\/5\/1457\/65476365\/c6mb00077k.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T20:37:54Z","timestamp":1767904674000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article\/12\/5\/1457\/8327342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,2]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,3,2]]}},"URL":"https:\/\/doi.org\/10.1039\/c6mb00077k","relation":{},"ISSN":["1742-2051","1742-206X"],"issn-type":[{"value":"1742-2051","type":"electronic"},{"value":"1742-206X","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,5,1]]},"published":{"date-parts":[[2016,3,2]]},"assertion":[{"value":"This document is Similarity Check deposited","name":"similarity_check","explanation":{"URL":"https:\/\/www.crossref.org\/services\/similarity-check\/"},"group":{"name":"similarity_check","label":"SIMILARITY CHECK"}},{"value":"Supplementary Information","URL":"https:\/\/doi.org\/10.1039\/C6MB00077K","name":"related_data","group":{"name":"related_data","label":"RELATED DATA"}},{"value":"The Royal Society of Chemistry has an exclusive publication licence for this journal","name":"copyright_licence","group":{"name":"copyright_licensing","label":"COPYRIGHT AND LICENSING"}},{"value":"Single-blind","order":2,"name":"peer_review_method","group":{"name":"peer_review_method","label":"PEER REVIEW METHOD"}},{"value":"Received 30 January 2016; Accepted 2 March 2016; Accepted Manuscript published 2 March 2016; Advance Article published 11 March 2016; Version of Record published 26 April 2016","order":1,"name":"history","group":{"name":"publication_history","label":"PUBLICATION HISTORY"}}]}}