{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T03:31:11Z","timestamp":1767929471824,"version":"3.49.0"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T00:00:00Z","timestamp":1538092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CHE-1726332"],"award-info":[{"award-number":["CHE-1726332"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005278","name":"Universidad de Antioquia","doi-asserted-by":"publisher","award":["CODI-CIQF-217"],"award-info":[{"award-number":["CODI-CIQF-217"]}],"id":[{"id":"10.13039\/501100005278","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Small molecule inhibitors of snake venom metalloproteinases (SVMPs) could provide a means to rapidly halt the progression of local tissue damage following viperid snake envenomations. In this study, we examine the ability of candidate compounds based on a pentacyclic triterpene skeleton to inhibit SVMPs. We leverage molecular dynamics simulations to estimate the free energies of the candidate compounds for binding to BaP1, a P-I type SVMP, and compare these results with experimental assays of proteolytic activity inhibition in a homologous enzyme (Batx-I). Both simulation and experiment suggest that betulinic acid is the most active candidate, with the simulations predicting a standard binding free energy of     \u0394  G \u2218  = \u2212 11.0 \u00b1 1.4     kcal\/mol. The simulations also reveal the atomic interactions that underlie binding between the triterpenic acids and BaP1, most notably the electrostatic interaction between carboxylate groups of the compounds and the zinc cofactor of BaP1. Together, our simulations and experiments suggest that occlusion of the S1     \u2032     subsite is essential for inhibition of proteolytic activity. While all active compounds make hydrophobic contacts in the S1     \u2032     site,    \u03b2   -boswellic acid, with its distinct carboxylate position, does not occlude the S1     \u2032     site in simulation and exhibits negligible activity in experiment.<\/jats:p>","DOI":"10.3390\/toxins10100397","type":"journal-article","created":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T13:37:58Z","timestamp":1538141878000},"page":"397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Interactions between Triterpenes and a P-I Type Snake Venom Metalloproteinase: Molecular Simulations and Experiments"],"prefix":"10.3390","volume":"10","author":[{"given":"Lina Mar\u00eda","family":"Preciado","sequence":"first","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Medell\u00edn, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime Andr\u00e9s","family":"Perea\u00f1ez","sequence":"additional","affiliation":[{"name":"Programa de Ofidismo\/Escorpionismo, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia UdeA, Medell\u00edn, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ettayapuram Ramaprasad","family":"Azhagiya Singam","sequence":"additional","affiliation":[{"name":"Institute of Computational Comparative Medicine, Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-1260","authenticated-orcid":false,"given":"Jeffrey","family":"Comer","sequence":"additional","affiliation":[{"name":"Institute of Computational Comparative Medicine, Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tasoulis, T., and Isbister, G.K. (2017). A review and database of snake venom proteomes. Toxins, 9.","DOI":"10.3390\/toxins9090290"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.toxicon.2012.09.004","article-title":"Snake venom metalloproteinases","volume":"62","author":"Markland","year":"2013","journal-title":"Toxicon"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kini, R.M., and Koh, C.Y. (2016). Metalloproteases affecting blood coagulation, fibrinolysis and platelet aggregation from snake venoms: Definition and nomenclature of interaction sites. Toxins, 8.","DOI":"10.3390\/toxins8100284"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1111\/j.1742-4658.2008.06466.x","article-title":"Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity","volume":"275","author":"Fox","year":"2008","journal-title":"FEBS J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.toxicon.2005.02.029","article-title":"Hemorrhage induced by snake venom metalloproteinases: biochemical and biophysical mechanisms involved in microvessel damage","volume":"45","author":"Rucavado","year":"2005","journal-title":"Toxicon"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J.M., Escalante, T., Rucavado, A., Herrera, C., and Fox, J.W. (2016). A comprehensive view of the structural and functional alterations of extracellular matrix by snake venom metalloproteinases (SVMPs): Novel perspectives on the pathophysiology of envenoming. Toxins, 8.","DOI":"10.3390\/toxins8100304"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Baldo, C., Jamora, C., Yamanouye, N., Zorn, T.M., and Moura-da Silva, A.M. (2010). Mechanisms of vascular damage by hemorrhagic snake venom metalloproteinases: Tissue distribution and in situ hydrolysis. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000727"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1590\/S0074-02762005000900031","article-title":"Inflammatory effects of snake venom metalloproteinases","volume":"100","author":"Teixeira","year":"2005","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hsu, C.C., and Huang, T.F. (2010). Biological activities of snake venom metalloproteinases on platelets, neutrophils, endothelial cells, and extracellular matrices. Toxins and Hemostasis, Springer.","DOI":"10.1007\/978-90-481-9295-3_41"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/S0300-9084(00)01163-9","article-title":"Snake venom metalloproteinases: Their role in the pathogenesis of local tissue damage","volume":"82","author":"Rucavado","year":"2000","journal-title":"Biochimie"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0041-0101(90)90011-U","article-title":"Effect of storage temperature on the stability of the liquid polyvalent antivenom produced in Costa Rica","volume":"28","author":"Rojas","year":"1990","journal-title":"Toxicon"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.toxicon.2009.01.012","article-title":"Stability of equine IgG antivenoms obtained by caprylic acid precipitation: Towards a liquid formulation stable at tropical room temperature","volume":"53","author":"Segura","year":"2009","journal-title":"Toxicon"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/S0041-0101(98)00145-7","article-title":"Neutralization of local tissue damage induced by Bothrops asper (terciopelo) snake venom","volume":"36","author":"Rojas","year":"1998","journal-title":"Toxicon"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Knudsen, C., and Laustsen, A.H. (2018). Recent Advances in Next Generation Snakebite Antivenoms. Trop. Med. Infect. Dis., 3.","DOI":"10.20944\/preprints201803.0227.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1007\/s10875-012-9735-7","article-title":"Matrix metalloproteinases: A review of their structure and role in systemic sclerosis","volume":"32","author":"Peng","year":"2012","journal-title":"J. Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0006-2952(00)00302-6","article-title":"Effectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by BaP1, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper","volume":"60","author":"Escalante","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.toxicon.2006.11.020","article-title":"Neutralization of the haemorrhagic activities of viperine snake venoms and venom metalloproteinases using synthetic peptide inhibitors and chelators","volume":"49","author":"Howes","year":"2007","journal-title":"Toxicon"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.toxicon.2014.11.224","article-title":"Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom","volume":"93","author":"Urs","year":"2015","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.biochi.2015.11.031","article-title":"A novel synthetic quinolinone inhibitor presents proteolytic and hemorrhagic inhibitory activities against snake venom metalloproteases","volume":"121","author":"Baraldi","year":"2016","journal-title":"Biochimie"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1021\/acsmedchemlett.7b00186","article-title":"Structure-Based Discovery of Thiosemicarbazone Metalloproteinase Inhibitors for Hemorrhage Treatment in Snakebites","volume":"8","author":"Ferreira","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.3390\/toxins2102478","article-title":"Biological and pathological studies of rosmarinic acid as an inhibitor of hemorrhagic Trimeresurus flavoviridis (habu) venom","volume":"2","author":"Aung","year":"2010","journal-title":"Toxins"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.2174\/156802611797633438","article-title":"Protective effect of Schizolobium parahyba flavonoids against snake venoms and isolated toxins","volume":"11","author":"Vale","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cbi.2004.09.016","article-title":"Neo-clerodane diterpenoid, a new metalloprotease snake venom inhibitor from Baccharis trimera (Asteraceae): Anti-proteolytic and anti-hemorrhagic properties","volume":"150","author":"Santos","year":"2004","journal-title":"Chem. Biol. Interact."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.cbi.2017.12.001","article-title":"Betulinic, oleanolic and ursolic acids inhibit the enzymatic and biological effects induced by a PI snake venom metalloproteinase","volume":"279","author":"Preciado","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1021\/ml300068r","article-title":"Identification of new snake venom metalloproteinase inhibitors using compound screening and rational peptide design","volume":"3","author":"Gortat","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/j.1742-7843.2011.00725.x","article-title":"Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1, 3-Dihydroisobenzofuran- 5-Carbonitrile","volume":"109","author":"Sunitha","year":"2011","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Srinivasa, V., Sundaram, M.S., Anusha, S., Hemshekhar, M., Nayaka, S.C., Kemparaju, K., Girish, K.S., and Rangappa, K.S. (2014). Novel apigenin based small molecule that targets snake venom metalloproteases. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106364"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1021\/acs.jctc.7b00791","article-title":"New Coarse Variables for the Accurate Determination of Standard Binding Free Energies","volume":"13","author":"Fu","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6358","DOI":"10.1073\/pnas.1303186110","article-title":"Funnel metadynamics as accurate binding free-energy method","volume":"110","author":"Limongelli","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7467","DOI":"10.1021\/jp5015934","article-title":"Evaluation of generalized Born model accuracy for absolute binding free energy calculations","volume":"118","author":"Zeller","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1111\/j.1747-0285.2012.01369.x","article-title":"Free energy calculations on snake venom metalloproteinase BaP1","volume":"79","author":"Lingott","year":"2012","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1080\/07391102.2014.963146","article-title":"Identification of potent inhibitors against snake venom metalloproteinase (SVMP) using molecular docking and molecular dynamics studies","volume":"33","author":"Chinnasamy","year":"2015","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fmolb.2017.00087","article-title":"Recent developments and applications of the MMPBSA method","volume":"4","author":"Wang","year":"2018","journal-title":"Front. Mol. Biosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6825","DOI":"10.1073\/pnas.0409005102","article-title":"Calculation of Absolute Protein\u2013ligand Binding Free Energy from Computer Simulations","volume":"102","author":"Woo","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1021\/ct1001768","article-title":"Free Energy Perturbation Hamiltonian Replica-exchange Molecular Dynamics (FEP\/H-REMD) for Absolute Ligand Binding Free Energy Calculations","volume":"6","author":"Jiang","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9169","DOI":"10.1063\/1.1410978","article-title":"Calculating Free Energies Using Average Force","volume":"115","author":"Darve","year":"2001","journal-title":"J. Chem. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1021\/jp506633n","article-title":"The Adaptive Biasing Force Method: Everything You Always Wanted to Know But Were Afraid to Ask","volume":"119","author":"Comer","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1021\/bi9002315","article-title":"High-resolution crystal structure of the snake venom metalloproteinase BaP1 complexed with a peptidomimetic: Insight into inhibitor binding","volume":"48","author":"Lingott","year":"2009","journal-title":"Biochemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.toxicon.2010.06.016","article-title":"Isolation and biological characterization of Batx-I, a weak hemorrhagic and fibrinogenolytic PI metalloproteinase from Colombian Bothrops atrox venom","volume":"56","author":"Benjumea","year":"2010","journal-title":"Toxicon"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0031-9422(00)00229-6","article-title":"Plant natural products active against snake bite\u2014The molecular approach","volume":"55","author":"Mors","year":"2000","journal-title":"Phytochemistry."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/bs.mie.2015.07.023","article-title":"Fragment-based screening for enzyme inhibitors using calorimetry","volume":"Volume 567","author":"Recht","year":"2016","journal-title":"Methods in Enzymology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbamcr.2009.08.006","article-title":"To bind zinc or not to bind zinc: An examination of innovative approaches to improved metalloproteinase inhibition","volume":"1803","author":"Jacobsen","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jprot.2010.12.002","article-title":"High resolution analysis of snake venom metalloproteinase (SVMP) peptide bond cleavage specificity using proteome based peptide libraries and mass spectrometry","volume":"74","author":"Leme","year":"2011","journal-title":"J. Proteom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"425","DOI":"10.2174\/0929867013373417","article-title":"The design, structure, and therapeutic application of matrix metalloproteinase inhibitors","volume":"8","author":"Skiles","year":"2001","journal-title":"Curr. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbapap.2011.04.009","article-title":"Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM\/ADAMTS family proteins","volume":"1824","author":"Takeda","year":"2012","journal-title":"BBA-Proteins Proteom."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6445","DOI":"10.1063\/1.464809","article-title":"Free Energy, Entropy, and Internal Energy of Hydrophobic Interactions: Computer Simulations","volume":"98","author":"Smith","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9539","DOI":"10.1063\/1.1789935","article-title":"Calculation of the aqueous solvation energy and entropy, as well as free energy, of simple polar solutes","volume":"121","author":"Wan","year":"2004","journal-title":"J. Chem. Phys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1111\/j.1476-5381.2009.00604.x","article-title":"Ligand binding assays at equilibrium: Validation and interpretation","volume":"161","author":"Hulme","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.bbagen.2014.08.004","article-title":"CHARMM Additive and Polarizable Force Fields for Biophysics and Computer-aided Drug Design","volume":"1850","author":"Vanommeslaeghe","year":"2015","journal-title":"BBA-Gen. Subj."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.4331\/wjbc.v2.i1.14","article-title":"Gelatin degradation assay reveals MMP-9 inhibitors and function of O-glycosylated domain","volume":"2","author":"Vandooren","year":"2011","journal-title":"World J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM General Force Field (CGenFF) I: Bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1021\/ci3003649","article-title":"Automation of the CHARMM General Force Field (CGenFF) II: Assignment of bonded parameters and partial atomic charges","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the Additive CHARMM All-atom Protein Force Field Targeting Improved Sampling of the Backbone \u03d5, \u03c8 and Side-chain \u03c71 and \u03c72 Dihedral Angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM simulations using the CHARMM36 additive force field","volume":"12","author":"Lee","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1002\/jcc.20289","article-title":"Scalable molecular dynamics with NAMD","volume":"26","author":"Phillips","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/ct5010406","article-title":"Long-time-step molecular dynamics through hydrogen mass repartitioning","volume":"11","author":"Hopkins","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_65","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":"ref_66","first-page":"3345","article-title":"Using collective variables to drive molecular dynamics simulations","volume":"111","author":"Fiorin","year":"2013","journal-title":"Math. Probl. Eng."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/10\/10\/397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:23:03Z","timestamp":1760196183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/10\/10\/397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,28]]},"references-count":66,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["toxins10100397"],"URL":"https:\/\/doi.org\/10.3390\/toxins10100397","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,28]]}}}