Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes

FEBS Journal

Volumn 280, Issue 12, 2013, Pages 2785-2805

  Kopec̈, Wojciech ^a   Telenius, Jelena ^a   Khandelia, Himanshu ^a  

^a UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

Author keywords

anesthetics; cholesterol; curcumin; drug membrane interactions; drugs; lipid membrane; molecular dynamics, lateral pressure profile; plant extracts; terpenes

Indexed keywords

1,2 DILAUROYL SN GLYCERO 3 PHOSPHOCHOLINE; 1,2 DIMYRISTOYL SN GLYCERO 3 PHOSPHOCHOLINE; 1,2 DIPALMITOYL SN GLYCERO 3 PHOSPHO LEVO SERINE; 2 OLEOYL 1 PALMITOYLPHOSPHATIDYLCHOLINE; ANESTHETIC AGENT; ARTICAINE; BENZOCAINE; CAROTENOID; CHLORPROMAZINE; CURCUMIN; DIOLEOYLPHOSPHATIDYLCHOLINE; DIPALMITOYLPHOSPHATIDYLCHOLINE; FLAVONOID; FUSIDIC ACID; GLYCEROPHOSPHOLIPID; HALOTHANE; HYPERICIN; KETAMINE; LIDOCAINE; LOCAL ANESTHETIC AGENT; NONSTEROID ANTIINFLAMMATORY AGENT; PHENOTHIAZINE DERIVATIVE; PHOSPHATIDIC ACID; PHYTOSTEROL; PLANT MEDICINAL PRODUCT; PROPOFOL; SAPONIN DERIVATIVE; SIRAMESINE; STILBENOID; UNCLASSIFIED DRUG; UNINDEXED DRUG;

BINDING SITE; CONFORMATIONAL TRANSITION; DRUG INTERACTION; DRUG PENETRATION; DRUG PROTEIN BINDING; DRUG STRUCTURE; GENERAL ANESTHESIA; HUMAN; LIPID BILAYER; LIPID DRUG INTERACTION; LOCAL ANESTHESIA; MEMBRANE TRANSPORT; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; SKIN CANCER; STATIC ELECTRICITY; TUBERCULOSIS;

ANESTHETICS; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CELL MEMBRANE; HUMANS; HYDROGEN BONDING; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; LIPID BILAYERS; MEMBRANE FLUIDITY; MOLECULAR DYNAMICS SIMULATION; PLANT EXTRACTS; PLANTS, MEDICINAL;

EID: 84878746587     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/febs.12286     Document Type: Review

References (103)

1. MacCallum JL, &, Tieleman DP, (2008) Interactions between small molecules and lipid bilayers. Curr Top Membr 60, 227-256.
2. Fujiwara Y, Dixon JA, O'Hara F, Funder ED, Dixon DD, Rodriguez RA, Baxter RD, Herle B, Sach N, Collins MR, et al,. (2012) Practical and innate carbon-hydrogen functionalization of heterocycles. Nature 492, 95-99.
3. Sheridan RP, (2002) The most common chemical replacements in drug-like compounds. J Chem Inf Comput Sci 42, 103-108.
4. Thanacoody HK, (2007) Thioridazine: resurrection as an antimicrobial agent? Br J Clin Pharmacol 64, 566-574.
5. Cantor RS, (1997) The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry 36, 2339-2344.
6. Cafiso DS, (1998) Dipole potentials and spontaneous curvature: membrane properties that could mediate anesthesia. Toxicol Lett 101, 431-439.
7. Meyer KH, (1937) Contributions to the theory of narcosis. Trans Faraday Soc 33, 1062.
8. Overton CE, (1901) Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Fischer, Jena.
9. Mouritsen OG, (2005) Life-as a matter of fat, Springer, Berlin.
10. Hogberg CJ, Maliniak A, &, Lyubartsev AP, (2007) Dynamical and structural properties of charged and uncharged lidocaine in a lipid bilayer. Biophys Chem 125, 416-424.
11. Hogberg CJ, &, Lyubartsev AP, (2008) Effect of local anesthetic lidocaine on electrostatic properties of a lipid bilayer. Biophys J 94, 525-531.
12. Mojumdar EH, &, Lyubartsev AP, (2010) Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer. Biophys Chem 153, 27-35.
13. Rog T, Pasenkiewicz-Gierula M, Vattulainen I, &, Karttunen M, (2009) Ordering effects of cholesterol and its analogues. Biochem Biophys Acta 1788, 97-121.
14. Prates ET, Souza PCT, Pickholz M, &, Skaf MS, (2011) CHARMM-based parameterization of neutral articaine-a widely used local anesthetic. Int J Quantum Chem 111, 1339-1345.
15. Pickholz M, Fraceto LF, &, de Paula E, (2008) Distribution of neutral prilocaine in a phospholipid bilayer: insights from molecular dynamics simulations. Int J Quantum Chem 108, 2386-2391.
16. Bernardi RC, Gomes DEB, Gobato R, Taft CA, Ota AT, &, Pascutti PG, (2009) Molecular dynamics study of biomembrane/local anesthetics interactions. Mol Phys 107, 1437-1443.
17. Porasso RD, Bennett WFD, Oliveira-Costa SD, &, Cascales JJL, (2009) Study of the benzocaine transfer from aqueous solution to the interior of a biological membrane. J Phys Chem B 113, 9988-9994.
18. Cascales JJL, Costa SDO, &, Porasso RD, (2011) Thermodynamic study of benzocaine insertion into different lipid bilayers. J Chem Phys 135, 135103.
19. Griepernau B, Leis S, Schneider MF, Sikor M, Steppich D, &, Bockmann RA, (2007) 1-alkanols and membranes: a story of attraction. Biochim Biophys Acta 1768, 2899-2913.
20. Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, &, Corringer PJ, (2011) X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469, 428-431.
21. Jerabek H, Pabst G, Rappolt M, &, Stockner T, (2010) Membrane-mediated effect on ion channels induced by the anesthetic drug ketamine. J Am Chem Soc 132, 7990-7997.
22. Samuli Ollila OH, Rog T, Karttunen M, &, Vattulainen I, (2007) Role of sterol type on lateral pressure profiles of lipid membranes affecting membrane protein functionality: comparison between cholesterol, desmosterol, 7-dehydrocholesterol and ketosterol. J Struct Biol 159, 311-323.
23. Koubi L, Tarek M, Bandyopadhyay S, Klein ML, &, Scharf D, (2001) Membrane structural perturbations caused by anesthetics and nonimmobilizers: a molecular dynamics investigation. Biophys J 81, 3339-3345.
24. Tu KM, Matubayasi N, Liang KK, Todorov IT, Chan SL, &, Chau PL, (2012) A possible molecular mechanism for the pressure reversal of general anaesthetics: aggregation of halothane in POPC bilayers at high pressure. Chem Phys Lett 543, 148-154.
25. Seeger HM, Gudmundsson ML, &, Heimburg T, (2007) How anesthetics, neurotransmitters, and antibiotics influence the relaxation processes in lipid membranes. J Phys Chem B 111, 13858-13866.
26. Johnson FH, &, Flagler EA, (1950) Hydrostatic pressure reversal of narcosis in tadpoles. Science 112, 91-92.
27. Miller KW, Paton WDM, Smith RA, &, Smith EB, (1973) Pressure reversal of general anesthesia and critical volume hypothesis. Mol Pharmacol 9, 131-143.
28. Chau PL, Tu KM, Liang KK, Todorov IT, Roser SJ, Barker R, &, Matubayasi N, (2012) The effect of pressure on halothane binding to hydrated DMPC bilayers. Mol Phys 110, 1461-1467.
29. Yamamoto E, Akimoto T, Shimizu H, Hirano Y, Yasui M, &, Yasuoka K, (2012) Diffusive nature of xenon anesthetic changes properties of a lipid bilayer: molecular dynamics simulations. J Phys Chem B 116, 8989-8995.
30. Orlowski A, Grzybek M, Bunker A, Pasenkiewicz-Gierula M, Vattulainen I, Mannisto PT, &, Rog T, (2012) Strong preferences of dopamine and l -dopa towards lipid head group: importance of lipid composition and implication for neurotransmitter metabolism. J Neurochem 122, 681-690.
31. Cantor RS, (2003) Receptor desensitization by neurotransmitters in membranes: are neurotransmitters the endogenous anesthetics? Biochemistry 42, 11891-11897.
32. Brender JR, McHenry AJ, &, Ramamoorthy A, (2012) Does cholesterol play a role in the bacterial selectivity of antimicrobial peptides? Front Immunol 3, 195.
33. Matsuzaki K, Sugishita K, Fujii N, &, Miyajima K, (1995) Molecular basis for membrane selectivity of an antimicrobial peptide, magainin-2. Biochemistry 34, 3423-3429.
34. Henriksen J, Rowat AC, Brief E, Hsueh YW, Thewalt JL, Zuckermann MJ, &, Ipsen JH, (2006) Universal behavior of membranes with sterols. Biophys J 90, 1639-1649.
35. Donnelly MT, &, Hawkey CJ, (1997) COX-II inhibitors-a new generation of safer NSAIDs? Aliment Pharmacol Ther 11, 227-236.
36. Chan AT, Ogino S, &, Fuchs CS, (2009) Aspirin use and survival after diagnosis of colorectal cancer. J Am Med Assoc 302, 649-659.
37. Hebert PR, &, Hennekens CH, (2000) An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease. Arch Intern Med 160, 3123-3127.
38. Stewart WF, Kawas C, Corrada M, &, Metter EJ, (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48, 626-632.
39. Allison MC, Howatson AG, Torrance CJ, Lee FD, &, Russell RI, (1992) Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 327, 749-754.
40. Rich M, &, Scheiman JM, (2000) Nonsteroidal anti-inflammatory drug gastropathy at the new millennium: mechanisms and prevention. Semin Arthritis Rheum 30, 167-179.
41. Boggara MB, &, Krishnamoorti R, (2010) Partitioning of nonsteroidal antiinflammatory drugs in lipid membranes: a molecular dynamics simulation study. Biophys J 98, 586-595.
42. Lichtenberger LM, Zhou Y, Jayaraman V, Doyen JR, O'Neil RG, Dial EJ, Volk DE, Gorenstein DG, Boggara MB, &, Krishnamoorti R, (2012) Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine. Biochim Biophys Acta 1821, 994-1002.
43. Boggara MB, &, Krishnamoorti R, (2010) Small-angle neutron scattering studies of phospholipid-NSAID adducts. Langmuir 26, 5734-5745.
44. Song YH, Guallar V, &, Baker NA, (2005) Molecular dynamics simulations of salicylate effects on the micro- and mesoscopic properties of a dipalmitoylphosphatidylcholine bilayer. Biochemistry 44, 13425-13438.
45. Fox CB, Horton RA, &, Harris JM, (2006) Detection of drug-membrane interactions in individual phospholipid vesicles by confocal Raman microscopy. Anal Chem 78, 4918-4924.
46. Khandelia H, Witzke S, &, Mouritsen OG, (2010) Interaction of salicylate and a terpenoid plant extract with model membranes: reconciling experiments and simulations. Biophys J 99, 3887-3894.
47. Sachlos E, Risueno RM, Laronde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, et al,. (2012) Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149, 1284-1297.
48. Amaral L, Kristiansen JE, Viveiros M, &, Atouguia J, (2001) Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J Antimicrob Chemother 47, 505-511.
49. Sharma S, &, Singh A, (2011) Phenothiazines as anti-tubercular agents: mechanistic insights and clinical implications. Expert Opin Investig Drugs 20, 1665-1676.
50. Rodrigues L, Sampaio D, Couto I, Machado D, Kern WV, Amaral L, &, Viveiros M, (2009) The role of efflux pumps in macrolide resistance in Mycobacterium avium complex. Int J Antimicrob Agents 34, 529-533.
51. Pickholz M, Oliveira ON, &, Skaf MS, (2006) Molecular dynamics simulations of neutral chlorpromazine in zwitterionic phospholipid monolayers. J Phys Chem B 110, 8804-8814.
52. 31P NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. Biochim Biophys Acta 507, 185-197.
53. Hendrich AB, Wesołowska O, Komorowska M, Motohashi N, &, Michalak K, (2002) The alterations of lipid bilayer fluidity induced by newly synthesized phenothiazine derivative. Biophys Chem 98, 275-285.
54. Parry MJ, Alakoskela JM, Khandelia H, Kumar SA, Jaattela M, Mahalka AK, &, Kinnunen PK, (2008) High-affinity small molecule-phospholipid complex formation: binding of siramesine to phosphatidic acid. J Am Chem Soc 130, 12953-12960.
55. Chowdary TK, Raman B, Ramakrishna T, &, Rao CM, (2007) Interaction of mammalian Hsp22 with lipid membranes. Biochem J 401, 437-445.
56. Steed PM, &, Chow AHM, (2001) Intracellular signaling by phospholipase D as a therapeutic target. Curr Pharm Biotechnol 2, 241-256.
57. Chew CF, Guy A, &, Biggin PC, (2008) Distribution and dynamics of adamantanes in a lipid bilayer. Biophys J 95, 5627-5636.
58. Falck E, Hautala JT, Karttunen M, Kinnunen PKJ, Patra M, Saaren-Seppala H, Vattulainen I, Wiedmer SK, &, Holopainen JM, (2006) Interaction of fusidic acid with lipid membranes: implications to the mechanism of antibiotic activity. Biophys J 91, 1787-1799.
59. Kyrychenko A, &, Waluk J, (2008) Distribution and favorable binding sites of pyrroloquinoline and its analogues in a lipid bilayer studied by molecular dynamics simulations. Biophys Chem 136, 128-135.
60. Orsi M, &, Essex JW, (2010) Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics. Soft Matter 6, 3797-3808.
61. Tapsell LC, Hemphill I, Cobiac L, Patch CS, Sullivan DR, Fenech M, Roodenrys S, Keogh JB, Clifton PM, Williams PG, et al,. (2006) Health benefits of herbs and spices: the past, the present, the future. Med J Aust 185, S4-S24.
62. Lai PK, &, Roy J, (2004) Antimicrobial and chemopreventive properties of herbs and spices. Curr Med Chem 11, 1451-1460.
63. Fabricant DS, &, Farnsworth NR, (2001) The value of plants used in traditional medicine for drug discovery. Environ Health Perspect 109, 69-75.
64. Wu X, Gu L, Prior RL, &, McKay S, (2004) Characterization of anthocyanins and proanthocyanidins in some cultivars of Ribes, Aronia, and Sambucus and their antioxidant capacity. J Agric Food Chem 52, 7846-7856.
65. Aggarwal BB, Sundaram C, Malani N, &, Ichikawa H, (2007) Curcumin: the Indian solid gold. Adv Exp Med Biol 595, 1-75.
66. Nitta M, Lee JK, Kang CW, Katsuta M, Yasumoto S, Liu D, Nagamine T, &, Ohnishi O, (2005) The distribution of Perilla species. Genet Resour Crop Evol 52, 797-804.
67. Hjort Ipsen J, Karlström G, Mourtisen OG, Wennerström H, &, Zuckermann MJ, (1987) Phase equilibria in the phosphatidylcholine-cholesterol system. Biochim Biophys Acta 905, 162-172.
68. 2H nuclear magnetic resonance study of phosphatidylcholine/cholesterol interactions: characterization of liquid-gel phases. Biochemistry 32, 13277-13287.
69. Hui SW, &, He NB, (1983) Molecular organization in cholesterol-lecithin bilayers by X-ray and electron diffraction measurements. Biochemistry 22, 1159-1164.
70. 2H nuclear magnetic resonance and differential scanning calorimetry. Biochemistry 29, 451-464.
71. Mannock DA, Lewis RN, McMullen TP, &, McElhaney RN, (2010) The effect of variations in phospholipid and sterol structure on the nature of lipid-sterol interactions in lipid bilayer model membranes. Chem Phys Lipids 163, 403-448.
72. Hac-Wydro K, Lenartowicz R, &, Dynarowicz-Łatka P, (2013) The influence of plant stanol (β-sitostanol) on inner leaflet of human erythrocytes membrane modeled with the Langmuir monolayer technique. Colloids Surf B Biointerfaces 102, 178-188.
73. Rog T, Stimson LM, Pasenkiewicz-Gierula M, Vattulainen I, &, Karttunen M, (2008) Replacing the cholesterol hydroxyl group with the ketone group facilitates sterol flip-flop and promotes membrane fluidity. J Phys Chem B 112, 1946-1952.
74. Silva C, Aranda FJ, Ortiz A, Martinez V, Carvajal M, &, Teruel JA, (2011) Molecular aspects of the interaction between plants sterols and DPPC bilayers: an experimental and theoretical approach. J Colloid Interface Sci 358, 192-201.
75. Francis G, Kerem Z, Makkar HP, &, Becker K, (2002) The biological action of saponins in animal systems: a review. Br J Nutr 88, 587-605.
76. Osbourn A, Goss RJ, &, Field RA, (2011) The saponins: polar isoprenoids with important and diverse biological activities. Nat Prod Rep 28, 1261-1268.
77. Lin F, &, Wang R, (2010) Hemolytic mechanism of dioscin proposed by molecular dynamics simulations. J Mol Model 16, 107-118.
78. Milgate J, &, Roberts DCK, (1995) The nutritional and biological significance of saponins. Nutr Res 15, 1223-1249.
79. Cushnie TP, &, Lamb AJ, (2011) Recent advances in understanding the antibacterial properties of flavonoids. Int J Antimicrob Agents 38, 99-107.
80. Zaveri NT, (2006) Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci 78, 2073-2080.
81. Sirk TW, Brown EF, Sum AK, &, Friedman M, (2008) Molecular dynamics study on the biophysical interactions of seven green tea catechins with lipid bilayers of cell membranes. J Agric Food Chem 56, 7750-7758.
82. Sirk TW, Brown EF, Friedman M, &, Sum AK, (2009) Molecular binding of catechins to biomembranes: relationship to biological activity. J Agric Food Chem 57, 6720-6728.
83. Raghunathan M, Zubovski Y, Venable RM, Pastor RW, Nagle JF, &, Tristram-Nagle S, (2012) Structure and elasticity of lipid membranes with genistein and daidzein bioflavinoids using X-ray scattering and MD simulations. J Phys Chem B 116, 3918-3927.
84. Kosinova P, Berka K, Wykes M, Otyepka M, &, Trouillas P, (2012) Positioning of antioxidant quercetin and its metabolites in lipid bilayer membranes: implication for their lipid-peroxidation inhibition. J Phys Chem B 116, 1309-1318.
85. Sinha R, Gadhwal MK, Joshi UJ, SrivaStava S, &, Govil G, (2011) Interaction of quercetin with DPPC model membrane: molecular dynamic simulation, DSC and multinuclear NMR studies. J Indian Chem Soc 88, 1203-1210.
86. Eriksson ESE, dos Santos DJVA, Guedes RC, &, Eriksson LA, (2009) Properties and permeability of hypericin and brominated hypericin in lipid membranes. J Chem Theory Comput 5, 3139-3149.
87. Eriksson ESE, &, Eriksson LA, (2011) The influence of cholesterol on the properties and permeability of hypericin derivatives in lipid membranes. J Chem Theory Comput 7, 560-574.
88. Hatcher H, Planalp R, Cho J, Torti FM, &, Torti SV, (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65, 1631-1652.
89. Karewicz A, Bielska D, Gzyl-Malcher B, Kepczynski M, Lach R, &, Nowakowska M, (2011) Interaction of curcumin with lipid monolayers and liposomal bilayers. Colloids Surf B Biointerfaces 88, 231-239.
90. Barry J, Fritz M, Brender JR, Smith PES, Lee D-K, &, Ramamoorthy A, (2009) Determining the effects of lipophilic drugs on membrane structure by solid-state NMR spectroscopy: the case of the antioxidant curcumin. J Am Chem Soc 131, 4490-4498.
91. Ingolfsson HI, Koeppe RE II, &, Andersen OS, (2007) Curcumin is a modulator of bilayer material properties. Biochemistry 46, 10384-10391.
92. Fabris S, Momo F, Ravagnan G, &, Stevanato R, (2008) Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes. Biophys Chem 135, 76-83.
93. Koukoulitsa C, Durdagi S, Siapi E, Villalonga-Barber C, Alexi X, Steele BR, Micha-Screttas M, Alexis MN, Tsantili-Kakoulidou A, &, Mavromoustakos T, (2011) Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity. Eur Biophys J 40, 865-875.
94. Okulski W, Sujak A, &, Gruszecki WI, (2008) Dipalmitoylphosphatidylcholine membranes modified with carotenoid pigment lutein: experiment versus Monte Carlo simulation study of the membrane organization. Biochim Biophys Acta 1778, 2105-2118.
95. Muddana HS, Chiang HH, &, Butler PJ, (2012) Tuning membrane phase separation using nonlipid amphiphiles. Biophys J 102, 489-497.
96. Qin SS, &, Yu ZW, (2011) Molecular dynamics simulations of α-tocopherol in model biomembranes. Acta Phys-Chim Sin 27, 213-227.
97. Siwko ME, de Vries AH, Mark AE, Kozubek A, &, Marrink SJ, (2009) Disturb or stabilize? A molecular dynamics study of the effects of resorcinolic lipids on phospholipid bilayers. Biophys J 96, 3140-3153.
98. Witzke S, Duelund L, Kongsted J, Petersen M, Mouritsen OG, &, Khandelia H, (2010) Inclusion of terpenoid plant extracts in lipid bilayers investigated by molecular dynamics simulations. J Phys Chem B 114, 15825-15831.
99. Peters GH, Dahmen-Levison U, De Meijere K, Brezesinski G, Toxvaerd S, Möhwald H, Svendsen A, &, Kinnunen PKJ, (2000) Influence of surface properties of mixed monolayers on lipolytic hydrolysis. Langmuir 16, 2779-2788.
100. Österberg T, Svensson M, &, Lundahl P, (2001) Chromatographic retention of drug molecules on immobilised liposomes prepared from egg phospholipids and from chemically pure phospholipids. Eur J Pharm Sci 12, 427-439.
101. Bahri MA, Seret A, Hans P, Piette J, Deby-Dupont G, &, Hoebeke M, (2007) Does propofol alter membrane fluidity at clinically relevant concentrations? An ESR spin label study. Biophys Chem 129, 82-91.
102. Trudell JR, Payan DG, Chin JH, &, Cohen EN, (1975) The antagonistic effect of an inhalation anesthetic and high pressure on the phase diagram of mixed dipalmitoyl dimyristoylphosphatidylcholine bilayers. Proc Natl Acad Sci USA 72, 210-213.
103. Neale C, Bennett WFD, Tieleman DP, &, Pomes R, (2011) Statistical Convergence of Equilibrium Properties in Simulations of Molecular Solutes Embedded in Lipid Bilayers. J Chem Theory Comput 7, 4175-4188.