Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs

Current Medicinal Chemistry

Volumn 20, Issue 1, 2013, Pages 22-38

  Sadiq, S K ^a   Guixa Gonzalez R ^a   Dainese, E ^b,c   Pastor, M ^a   De Fabritiis, G ^a   Selent, J ^a  

^a UNIVERSITAT POMPEU FABRA   (Spain)

^b UNIVERSITY OF TERAMO   (Italy)

^c IRCCS FONDAZIONE SANTA LUCIA   (Italy)

Author keywords

G protein coupled receptor; GPCR regulation; Hydrophobic mismatch; Lipid bilayer; Molecular dynamics; Oligomerization

Indexed keywords

G PROTEIN COUPLED RECEPTOR; MEMBRANE LIPID;

DIFFUSION COEFFICIENT; HUMAN; INTERDIGITATING CELL; LIPID BILAYER; LIPID MEMBRANE; MEMBRANE STRUCTURE; MOLECULAR DYNAMICS; MOLECULAR MODEL; MONTE CARLO METHOD; OLIGOMERIZATION; PROTEIN FUNCTION; PROTEIN LIPID INTERACTION; REVIEW;

ANIMALS; HUMANS; LIPID BILAYERS; MEMBRANE LIPIDS; MOLECULAR DYNAMICS SIMULATION; PROTEIN MULTIMERIZATION; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84872926726     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/09298673130104     Document Type: Review

References (208)

1. Horn, F.; Bettler, E.; Oliveira, L.; Campagne, F.; Cohen, F. E.; Vriend, G. GPCRDB information system for G protein-coupled receptors. Nucleic Acids Res. 2003, 31, 294-297.
2. Müller, G. Towards 3D structures of G protein-coupled receptors: a multidisciplinary approach. Curr. Med. Chem. 2000, 7, 861-888.
3. Moffett, S.; Brown, D. A.; Linder, M. E. Lipid-dependent targeting of G proteins into rafts. J. Biol. Chem. 2000, 275, 2191-2198.
4. Seno, K.; Kishimoto, M.; Abe, M.; Higuchi, Y.; Mieda, M.; Owada, Y.; Yoshiyama, W.; Liu, H.; Hayashi, F. Light-and guanosine 5'-3-O-(thio) triphosphate-sensitive localization of a G protein and its effector on detergent-resistant membrane rafts in rod photoreceptor outer segments. J. Biol. Chem. 2001, 276, 20813-20816.
5. Rybin, V. O.; Xu, X.; Lisanti, M. P.; Steinberg, S. F. Differential targeting of beta -adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway. J. Biol. Chem. 2000, 275, 41447-41457.
6. Kalipatnapu, S.; Chattopadhyay, A. Membrane organization and function of the serotonin(1A) receptor. Cell. Mol. Neurobiol. 2007, 27, 1097-1116.
7. Xiang, Y.; Rybin, V. O.; Steinberg, S. F.; Kobilka, B. Caveolar localization dictates physiologic signaling of beta 2-adrenoceptors in neonatal cardiac myocytes. J. Biol. Chem. 2002, 277, 34280-34286.
8. Feron, O.; Smith, T. W.; Michel, T.; Kelly, R. A. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J. Biol. Chem. 1997, 272, 17744-17748.
9. Ushio-Fukai, M.; Hilenski, L.; Santanam, N.; Becker, P. L.; Ma, Y.; Griendling, K. K.; Alexander, R. W. Cholesterol depletion inhibits epidermal growth factor receptor transactivation by angiotensin II in vascular smooth muscle cells: role of cholesterol-rich microdomains and focal adhesions in angiotensin II signaling. J. Biol. Chem. 2001, 276, 48269-48275.
10. Sabourin, T.; Bastien, L.; Bachvarov, D. R.; Marceau, F. Agonist-induced translocation of the kinin B(1) receptor to caveolae-related rafts. Mol. Pharmacol. 2002, 61, 546-553.
11. Roettger, B. F.; Rentsch, R. M.; Hadac, E. M.; Hellen, E. H.; Burghardt, T. P.; Miller, L. J. Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell. J. Cell Biol. 1995, 130, 579-590.
12. Okamoto, Y.; Ninomiya, H.; Miwa, S.; Masaki, T. Cholesterol oxidation switches the internalization pathway of endothelin receptor type A from caveolae to clathrin-coated pits in Chinese hamster ovary cells. J. Biol. Chem. 2000, 275, 6439-6446.
13. Bari, M.; Battista, N.; Fezza, F.; Finazzi-Agrò, A.; Maccarrone, M. Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J. Biol. Chem. 2005, 280, 12212-12220.
14. Sarnataro, D.; Grimaldi, C.; Pisanti, S.; Gazzerro, P.; Laezza, C.; Zurzolo, C.; Bifulco, M. Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells. FEBS Lett. 2005, 579, 6343-6349.
15. Sarnataro, D.; Pisanti, S.; Santoro, A.; Gazzerro, P.; Malfitano, A. M.; Laezza, C.; Bifulco, M. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol. Pharmacol. 2006, 70, 1298-1306.
16. Oddi, S.; Dainese, E.; Fezza, F.; Lanuti, M.; Barcaroli, D.; De Laurenzi, V.; Centonze, D.; Maccarrone, M. Functional characterization of putative cholesterol binding sequence (CRAC) in human type-1 cannabinoid receptor. J. Neurochem. 2011, 116, 858-865.
17. Oddi, S.; Dainese, E.; Sandiford, S.; Fezza, F.; Lanuti, M.; Chiurchiù, V.; Totaro, A.; Catanzaro, G.; Barcaroli, D.; De Laurenzi, V.; Centonze, D.; Mukhopadhyay, S.; Selent, J.; Howlett, A. C.; Maccarrone, M. Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid receptor on membrane localization and signalling. Br. J. Pharmacol. 2012, 165, 2635-2651.
18. Bari, M.; Spagnuolo, P.; Fezza, F.; Oddi, S.; Pasquariello, N.; Finazzi-Agrò, A.; Maccarrone, M. Effect of lipid rafts on CB2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J. Immunol. 2006, 177, 4971-4980.
19. Rimmerman, N.; Hughes, H. V.; Bradshaw, H. B.; Pazos, M. X.; Mackie, K.; Prieto, A. L.; Walker, J. M. Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line. Br. J. Pharmacol. 2008, 153, 380-389.
20. Chun, M.; Liyanage, M. K.; Lisanti, M. P.; Lodish, H. F. Signal transduction of a G protein-coupled receptor in caveolae: colocalization of endothelin and its receptor with caveolin. Proc. Natl. Acad. Sci. M.S.A. 1994, 91, 11728-11732.
21. Klein, M.; Gimpl, G.; Fahrenholz, F. Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 1995, 34, 13784-13793.
22. Gimpl, G.; Fahrenholz, F. Human oxytocin receptors in cholesterol-rich vs. cholesterol-poor microdomains of the plasma membrane. Eur. J. Biochem. 2000, 267, 2483-2497.
23. Reversi, A.; Rimoldi, V.; Brambillasca, S.; Chini, B. Effects of cholesterol manipulation on the signaling of the human oxytocin receptor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006, 291, R861-869.
24. Wenk, M. R. The emerging field of lipidomics. Nat. Rev. Drug. Discov. 2005, 4, 594-610.
25. Wenk, M. R. Lipidomics: new tools and applications. Cell 2010, 143, 888-895.
26. Simons, K.; Gerl, M. J. Revitalizing membrane rafts: new tools and insights. Nat. Rev. Mol. Cell Biol. 2010, 11, 688-699.
27. Jacobson, K.; Mouritsen, O. G.; Anderson, R. G. W. Lipid rafts: at a crossroad between cell biology and physics. Nat. Cell Biol. 2007, 9, 7-14.
28. Dupuy, A. D.; Engelman, D. M. Protein area occupancy at the center of the red blood cell membrane. Proc. Natl. Acad. Sci. M.S.A. 2008, 105, 2848-2852.
29. Opekarová, M.; Tanner, W. Specific lipid requirements of membrane proteins-a putative bottleneck in heterologous expression. Biochim. Biophys. Acta 2003, 1610, 11-22.
30. Blom, T.; Somerharju, P.; Ikonen, E. Synthesis and biosynthetic trafficking of membrane lipids. Cold Spring Harb. Perspect. Biol. 2011, 3(8), a004713.
31. van Meer, G.; Voelker, D. R.; Feigenson, G. W. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 2008, 9, 112-124.
32. Hung, W.-.C.; Lee, M.-.T.; Chen, F.-Y.; Huang, H. W. The condensing effect of cholesterol in lipid bilayers. Biophys. J. 2007, 92, 3960-3967.
33. van Meer, G. Dynamic transbilayer lipid asymmetry. Cold Spring Harb. Perspect. Biol. 2011, 3(5), a004671.
34. Devaux, P. F.; Morris, R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic 2004, 5, 241-246.
35. Perlmutter, J. D.; Sachs, J. N. Interleaflet interaction and asymmetry in phase separated lipid bilayers: molecular dynamics simulations. J. Am. Chem. Soc. 2011, 133, 6563-6577.
36. Schmitz, G.; Grandl, M. Update on lipid membrane microdomains. Curr. Opin. Clin. Nutr. Metab. Care. 2008, 11, 106-112.
37. Lingwood, D.; Simons, K. Lipid rafts as a membrane-organizing principle. Science 2010, 327, 46-50.
38. Simons, K.; Vaz, W. L. C. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 269-295.
39. Berkowitz, M. L. Detailed molecular dynamics simulations of model biological membranes containing cholesterol. Biochim. Biophys. Acta 2009, 1788, 86-96.
40. Khelashvili, G. A.; Scott, H. L. Combined Monte Carlo and molecular dynamics simulation of hydrated 18:0 sphingomyelin-cholesterol lipid bilayers. J. Chem. Phys. 2004, 120, 9841-9847.
41. Sugár, I. P.; Biltonen, R. L. Lateral diffusion of molecules in two-component lipid bilayer: a Monte Carlo simulation study. J. Phys. Chem. B 2005, 109, 7373-7386.
42. Berkowitz, M. L. Detailed molecular dynamics simulations of model biological membranes containing cholesterol. Biochim. Biophys. Acta 2009, 1788, 86-96.
43. Sansom, M. S. P.; Scott, K. A.; Bond, P. J. Coarse-grained simulation: a high-throughput computational approach to membrane proteins. Biochem. Soc. Trans. 2008, 36, 27-32.
44. Klauda, J. B.; Venable, R. M.; Freites, J. A.; O'Connor, J. W.; Tobias, D. J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A. D., Jr.; Pastor, R. W. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 2010, 114, 7830-7843.
45. Hofsäss, C.; Lindahl, E.; Edholm, O. Molecular dynamics simulations of phospholipid bilayers with cholesterol. Biophys. J. 2003, 84, 2192-2206.
46. Mori, T.; Ogushi, F.; Sugita, Y. Analysis of lipid surface area in proteinmembrane systems combining Voronoi tessellation and Monte Carlo integration methods. J. Comput. Chem. 2012, 33, 286-293.
47. de Meyer, F.; Smit, B. Effect of cholesterol on the structure of a phospholipid bilayer. Proc. Natl. Acad. Sci. M.S.A. 2009, 106, 3654-3658.
48. Pitman, M. C.; Grossfield, A.; Suits, F.; Feller, S. E. Role of cholesterol and polyunsaturated chains in lipid-protein interactions: molecular dynamics simulation of rhodopsin in a realistic membrane environment. J. Am. Chem. Soc. 2005, 127, 4576-4577.
49. Vermeer, L. S.; de Groot, B. L.; Réat, V.; Milon, A.; Czaplicki, J. Acyl chain order parameter profiles in phospholipid bilayers: computation from molecular dynamics simulations and comparison with 2H NMR experiments. Eur. Biophys. J. 2007, 36, 919-931.
50. de Joannis, J.; Coppock, P. S.; Yin, F.; Mori, M.; Zamorano, A.; Kindt, J. T. Atomistic simulation of cholesterol effects on miscibility of saturated and unsaturated phospholipids: implications for liquid-ordered/liquid-disordered phase coexistence. J. Am. Chem. Soc. 2011, 133, 3625-3634.
51. Zhao, G.; Subbaiah, P. V.; Mintzer, E.; Chiu, S. W.; Jakobsson, E.; Scott, H. L. Molecular dynamic simulation study of cholesterol and conjugated double bonds in lipid bilayers. Chem. Phys. Lipids 2011, 164, 811-818.
52. Patra, M.; Karttunen, M.; Hyvönen, M. T.; Falck, E.; Lindqvist, P.; Vattulainen, I. Molecular dynamics simulations of lipid bilayers: major artifacts due to truncating electrostatic interactions. Biophys. J. 2003, 84, 3636-3645.
53. Pandit, S. A.; Scott, H. L. Multiscale simulations of heterogeneous model membranes. Biochim. Biophys. Acta 2009, 1788, 136-148.
54. Martinez-Seara, H.; Róg, T.; Karttunen, M.; Vattulainen, I.; Reigada, R. Cholesterol induces specific spatial and orientational order in cholesterol/phospholipid membranes. PLoS ONE 2010, 5, e11162.
55. Falck, E.; Patra, M.; Karttunen, M.; Hyvönen, M. T.; Vattulainen, I. Lessons of slicing membranes: interplay of packing, free area, and lateral diffusion in phospholipid/cholesterol bilayers. Biophys. J. 2004, 87, 1076-1091.
56. Lindblom, G.; Orädd, G. Lipid lateral diffusion and membrane heterogeneity. Biochim. Biophys. Acta 2009, 1788, 234-244.
57. Apajalahti, T.; Niemelä, P.; Govindan, P. N.; Miettinen, M. S.; Salonen, E.; Marrink, S. J.; Vattulainen, I. Concerted diffusion of lipids in raft-like membranes. Faraday Discuss. 2010, 144; 445-481.
58. Niemelä, P. S.; Miettinen, M. S.; Monticelli, L.; Hammaren, H.; Bjelkmar, P.; Murtola, T.; Lindahl, E.; Vattulainen, I. Membrane proteins diffuse as dynamic complexes with lipids. J. Am. Chem. Soc. 2010, 132, 7574-7575.
59. Fanelli, F.; De Benedetti, P. G. Update 1 of: computational modeling approaches to structure-function analysis of G protein-coupled receptors. Chem. Rev. 2011, 111, PR438-535.
60. Crozier, P. S.; Stevens, M. J.; Forrest, L. R.; Woolf, T. B. Molecular dynamics simulation of dark-adapted rhodopsin in an explicit membrane bilayer: coupling between local retinal and larger scale conformational change. J. Mol. Biol. 2003, 333, 493-514.
61. Feller, S. E.; Gawrisch, K.; Woolf, T. B. Rhodopsin exhibits a preference for solvation by polyunsaturated docosohexaenoic acid. J. Am. Chem. Soc. 2003, 125, 4434-4435.
62. Shim, J.-Y. Transmembrane helical domain of the cannabinoid CB1 receptor. Biophys. J. 2009, 96, 3251-3262.
63. Jardón-Valadez, E.; Ulloa-Aguirre, A.; Piñeiro, A. Modeling and molecular dynamics simulation of the human gonadotropin-releasing hormone receptor in a lipid bilayer. J. Phys. Chem. B 2008, 112, 10704-10713.
64. Lyman, E.; Higgs, C.; Kim, B.; Lupyan, D.; Shelley, J. C.; Farid, R.; Voth, G. A. A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A2A adenosine receptor. Structure 2009, 17, 1660-1668.
65. Cordomí, A.; Perez, J. J. Molecular dynamics simulations of rhodopsin in different one-component lipid bilayers. J. Phys. Chem. B 2007, 111, 7052-7063.
66. Pitman, M. C.; Grossfield, A.; Suits, F.; Feller, S. E. Role of cholesterol and polyunsaturated chains in lipid-protein interactions: molecular dynamics simulation of rhodopsin in a realistic membrane environment. J. Am. Chem. Soc. 2005, 127, 4576-4577.
67. Grossfield, A.; Feller, S. E.; Pitman, M. C. A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids. Proc. Natl. Acad. Sci. M.S.A. 2006, 103, 4888-4893.
68. Grossfield, A.; Feller, S. E.; Pitman, M. C. Contribution of omega-3 fatty acids to the thermodynamics of membrane protein solvation. J. Phys. Chem. B 2006, 110, 8907-8909.
69. Khelashvili, G.; Grossfield, A.; Feller, S. E.; Pitman, M. C.; Weinstein, H. Structural and dynamic effects of cholesterol at preferred sites of interaction with rhodopsin identified from microsecond length molecular dynamics simulations. Proteins 2009, 76, 403-417.
70. Olausson, B. E. S.; Grossfield, A.; Pitman, M. C.; Brown, M. F.; Feller, S. E.; Vogel, A. Molecular dynamics simulations reveal specific interactions of post-translational palmitoyl modifications with rhodopsin in membranes. J. Am. Chem. Soc. 2012, 134, 4324-4331.
71. Mondal, S.; Khelashvili, G.; Shan, J.; Andersen, O. S.; Weinstein, H. Quantitative modeling of membrane deformations by multihelical membrane proteins: application to G-protein coupled receptors. Biophys. J. 2011, 101, 2092-2101.
72. Shan, J.; Khelashvili, G.; Mondal, S.; Mehler, E. L.; Weinstein, H. Liganddependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties. PLoS Comput. Biol. 2012, 8, e1002473.
73. Michael F., B. In: Lipid Polymorphism and Membrane Properties; Academic Press, 1997; Vol. Vol. 44, pp. 285-356.
74. Botelho, A. V.; Gibson, N. J.; Thurmond, R. L.; Wang, Y.; Brown, M. F. Conformational energetics of rhodopsin modulated by nonlamellar-forming lipids. Biochemistry 2002, 41, 6354-6368.
75. Soubias, O.; Teague, W. E. Jr.; Hines, K. G.; Mitchell, D. C.; Gawrisch, K. Contribution of membrane elastic energy to rhodopsin function. Biophys. J. 2010, 99, 817-824.
76. Zaitseva, E.; Brown, M. F.; Vogel, R. Sequential rearrangement of interhelical networks upon rhodopsin activation in membranes: the Meta II(a) conformational substate. J. Am. Chem. Soc. 2010, 132, 4815-4821.
77. Mitchell, D. C.; Niu, S. L.; Litman, B. J. Optimization of receptor-G protein coupling by bilayer lipid composition I: kinetics of rhodopsin-transducin binding. J. Biol. Chem. 2001, 276, 42801-42806.
78. Niu, S. L.; Mitchell, D. C.; Litman, B. J. Optimization of receptor-G protein coupling by bilayer lipid composition II: formation of metarhodopsin IItransducin complex. J. Biol. Chem. 2001, 276, 42807-42811.
79. Niu, S. L.; Mitchell, D. C.; Litman, B. J. Manipulation of cholesterol levels in rod disk membranes by methyl-beta-cyclodextrin: effects on receptor activation. J. Biol. Chem. 2002, 277, 20139-20145.
80. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000, 289, 739-745.
81. Huber, T.; Botelho, A. V.; Beyer, K.; Brown, M. F. Membrane model for the G-protein-coupled receptor rhodopsin: hydrophobic interface and dynamical structure. Biophys. J. 2004, 86, 2078-2100.
82. Saam, J.; Tajkhorshid, E.; Hayashi, S.; Schulten, K. Molecular dynamics investigation of primary photoinduced events in the activation of rhodopsin. Biophys. J. 2002, 83, 3097-3112.
83. Lemaître, V.; Yeagle, P.; Watts, A. Molecular dynamics simulations of retinal in rhodopsin: from the dark-adapted state towards lumirhodopsin. Biochemistry 2005, 44, 12667-12680.
84. Liu, W.; Chun, E.; Thompson, A. A.; Chubukov, P.; Xu, F.; Katritch, V.; Han, G. W.; Roth, C. B.; Heitman, L. H.; IJzerman, A. P.; Cherezov, V.; Stevens, R. C. Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions. Science 2012, 337, 232-236.
85. Gibson, N. J.; Brown, M. F. Lipid headgroup and acyl chain composition modulate the MI-MII equilibrium of rhodopsin in recombinant membranes. Biochemistry 1993, 32, 2438-2454.
86. Soubias, O.; Gawrisch, K. Probing specific lipid-protein interaction by saturation transfer difference NMR spectroscopy. J. Am. Chem. Soc. 2005, 127, 13110-13111.
87. Alves, I. D.; Salgado, G. F. J.; Salamon, Z.; Brown, M. F.; Tollin, G.; Hruby, V. J. Phosphatidylethanolamine enhances rhodopsin photoactivation and transducin binding in a solid supported lipid bilayer as determined using plasmon-waveguide resonance spectroscopy. Biophys. J. 2005, 88, 198-210.
88. Polozova, A.; Litman, B. J. Cholesterol dependent recruitment of di22:6-PC by a G protein-coupled receptor into lateral domains. Biophys. J. 2000, 79, 2632-2643.
89. Bennett, M. P.; Mitchell, D. C. Regulation of membrane proteins by dietary lipids: effects of cholesterol and docosahexaenoic acid acyl chain-containing phospholipids on rhodopsin stability and function. Biophys. J. 2008, 95, 1206-1216.
90. Ruprecht, J. J.; Mielke, T.; Vogel, R.; Villa, C.; Schertler, G. F. X. Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004, 23, 3609-3620.
91. Schertler, G. F. X. Structure of rhodopsin and the metarhodopsin I photointermediate. Curr. Opin. Struct. Biol. 2005, 15, 408-415.
92. Cherezov, V.; Rosenbaum, D. M.; Hanson, M. A.; Rasmussen, S. G. F.; Thian, F. S.; Kobilka, T. S.; Choi, H.-.J.; Kuhn, P.; Weis, W. I.; Kobilka, B. K.; Stevens, R. C. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007, 318, 1258-1265.
93. Hanson, M. A.; Cherezov, V.; Griffith, M. T.; Roth, C. B.; Jaakola, V.-.P.; Chien, E. Y. T.; Velasquez, J.; Kuhn, P.; Stevens, R. C. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 2008, 16, 897-905.
94. Han, D. S.; Wang, S. X.; Weinstein, H. Active state-like conformational elements in the beta2-AR and a photoactivated intermediate of rhodopsin identified by dynamic properties of GPCRs. Biochemistry 2008, 47, 7317-7321.
95. Altenbach, C.; Cai, K.; Klein-Seetharaman, J.; Khorana, H. G.; Hubbell, W. L. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 65 in helix TM1 and residues in the sequence 306-319 at the cytoplasmic end of helix TM7 and in helix H8. Biochemistry 2001, 40, 15483-15492.
96. Altenbach, C.; Klein-Seetharaman, J.; Cai, K.; Khorana, H. G.; Hubbell, W. L. Structure and function in rhodopsin: mapping light-dependent changes in distance between residue 316 in helix 8 and residues in the sequence 60-75, covering the cytoplasmic end of helices TM1 and TM2 and their connection loop CL1. Biochemistry 2001, 40, 15493-15500.
97. Altenbach, C.; Kusnetzow, A. K.; Ernst, O. P.; Hofmann, K. P.; Hubbell, W. L. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proc. Natl. Acad. Sci. M.S.A. 2008, 105, 7439-7444.
98. Zezula, J.; Freissmuth, M. The A(2A)-adenosine receptor: a GPCR with unique features? Br. J. Pharmacol. 2008, 153 Suppl 1, S184-190.
99. Salom, D.; Lodowski, D. T.; Stenkamp, R. E.; Le Trong, I.; Golczak, M.; Jastrzebska, B.; Harris, T.; Ballesteros, J. A.; Palczewski, K. Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc. Natl. Acad. Sci. M.S.A. 2006, 103, 16123-16128.
100. O'Dowd, B. F.; Hnatowich, M.; Caron, M. G.; Lefkowitz, R. J.; Bouvier, M. Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J. Biol. Chem. 1989, 264, 7564-7569.
101. Reid, H. M.; Mulvaney, E. P.; Turner, E. C.; Kinsella, B. T. Interaction of the human prostacyclin receptor with Rab11: characterization of a novel Rab11 binding domain within alpha-helix 8 that is regulated by palmitoylation. J. Biol. Chem. 2010, 285, 18709-18726.
102. Gehret, A. M.; Jones, B. W.; Tran, P. N.; Cook, L. B.; Greuber, E. K.; Hinkle, P. M. Role of helix 8 of the thyrotropin-releasing hormone receptor in phosphorylation by G protein-coupled receptor kinase. Mol. Pharmacol. 2010, 77, 288-297.
103. Reid, H. M.; Kinsella, B. T. Palmitoylation of the TPbeta isoform of the human thromboxane A2 receptor. Modulation of G protein: effector coupling and modes of receptor internalization. Cell. Signal. 2007, 19, 1056-1070.
104. Blanpain, C.; Wittamer, V.; Vanderwinden, J. M.; Boom, A.; Renneboog, B.; Lee, B.; Le Poul, E.; El Asmar, L.; Govaerts, C.; Vassart, G.; Doms, R. W.; Parmentier, M. Palmitoylation of CCR5 is critical for receptor trafficking and efficient activation of intracellular signaling pathways. J. Biol. Chem. 2001, 276, 23795-23804.
105. Swift, S.; Leger, A. J.; Talavera, J.; Zhang, L.; Bohm, A.; Kuliopulos, A. Role of the PAR1 receptor 8th helix in signaling: the 7-8-1 receptor activation mechanism. J. Biol. Chem. 2006, 281, 4109-4116.
106. Miggin, S. M.; Lawler, O. A.; Kinsella, B. T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. 2003, 278, 6947-6958.
107. Periole, X.; Huber, T.; Marrink, S. J.; Sakmar, T. P. G protein-coupled receptors self-assemble in dynamics simulations of model bilayers. J. Am. Chem. Soc. 2007, 129, 10126-10132.
108. Mouritsen, O. G.; Bloom, M. Mattress model of lipid-protein interactions in membranes. Biophys. J. 1984, 46, 141-153.
109. Killian, J. A.; Nyholm, T. K. M. Peptides in lipid bilayers: the power of simple models. Curr. Opin. Struct. Biol. 2006, 16, 473-479.
110. Jensen, M. Ø.; Mouritsen, O. G. Lipids do influence protein function-the hydrophobic matching hypothesis revisited. Biochim. Biophys. Acta 2004, 1666, 205-226.
111. Yeagle, P. L.; Bennett, M.; Lemaître, V.; Watts, A. Transmembrane helices of membrane proteins may flex to satisfy hydrophobic mismatch. Biochim. Biophys. Acta 2007, 1768, 530-537.
112. Botelho, A. V.; Huber, T.; Sakmar, T. P.; Brown, M. F. Curvature and hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes. Biophys. J. 2006, 91, 4464-4477.
113. Huang, H. W. Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime. Biophys. J. 1986, 50, 1061-1070.
114. Nielsen, C.; Goulian, M.; Andersen, O. S. Energetics of Inclusion-Induced Bilayer Deformations. Biophys. J. 1998, 74, 1966-1983.
115. Guo, W.; Shi, L.; Filizola, M.; Weinstein, H.; Javitch, J. A. Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc. Natl. Acad. Sci. M.S.A. 2005, 102, 17495-17500.
116. Mancia, F.; Assur, Z.; Herman, A. G.; Siegel, R.; Hendrickson, W. A. Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep. 2008, 9, 363-369.
117. Fung, J. J.; Deupi, X.; Pardo, L.; Yao, X. J.; Velez-Ruiz, G. A.; Devree, B. T.; Sunahara, R. K.; Kobilka, B. K. Ligand-regulated oligomerization of beta(2)-adrenoceptors in a model lipid bilayer. EMBO J 2009, 28, 3315-3328.
118. Bruno, A.; Costantino, G.; de Fabritiis, G.; Pastor, M.; Selent, J. Membranesensitive conformational states of helix 8 in the metabotropic Glu2 receptor, a class C GPC.R. PLoS ONE 2012, 7, e42023.
119. Kaye, R. G.; Saldanha, J. W.; Lu, Z. L.; Hulme, E. C. Helix 8 of the M1 muscarinic acetylcholine receptor: scanning mutagenesis delineates a G protein recognition site. Mol. Pharmacol. 2011, 79, 701-709.
120. Kirchberg, K.; Kim, T. Y.; Möller, M.; Skegro, D.; Dasara Raju, G.; Granzin, J.; Büldt, G.; Schlesinger, R.; Alexiev, M. Conformational dynamics of helix 8 in the GPCR rhodopsin controls arrestin activation in the desensitization process. Proc. Natl. Acad. Sci. M.S.A. 2011, 108, 18690-18695.
121. Contreras, F. X.; Ernst, A. M.; Haberkant, P.; Björkholm, P.; Lindahl, E.; Gönen, B.; Tischer, C.; Elofsson, A.; von Heijne, G.; Thiele, C.; Pepperkok, R.; Wieland, F.; Brügger, B. Molecular recognition of a single sphingolipid species by a protein's transmembrane domain. Nature 2012, 481, 525-529.
122. Katritch, V.; Cherezov, V.; Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 2012, 33, 17-27.
123. Hanson, M. A.; Roth, C. B.; Jo, E.; Griffith, M. T.; Scott, F. L.; Reinhart, G.; Desale, H.; Clemons, B.; Cahalan, S. M.; Schuerer, S. C.; Sanna, M. G.; Han, G. W.; Kuhn, P.; Rosen, H.; Stevens, R. C. Crystal structure of a lipid G protein-coupled receptor. Science 2012, 335, 851-855.
124. Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Mathiesen, J. M.; Sunahara, R. K.; Pardo, L.; Weis, W. I.; Kobilka, B. K.; Granier, S. Crystal structure of the opioid receptor bound to a morphinan antagonist. Nature 2012.
125. Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X. P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human opioid receptor in complex with JDTic. Nature 2012, 485, 327-332.
126. Granier, S.; Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Weis, W. I.; Kobilka, B. K. Structure of the α-opioid receptor bound to naltrindole. Nature 2012, 485, 400-404.
127. Obiol-Pardo, C.; López, L.; Pastor, M.; Selent, J. Progress in the structural prediction of G protein-coupled receptors: D3 receptor in complex with eti clopride. Proteins 2010.
128. Kufareva, I.; Rueda, M.; Katritch, V.; participants of GPCR Dock 2010;
129. Stevens, R.; Abagyan, R. Status of GPCR modeling and docking as reflected by community wide GPCR Dock 2010 assessment. Proteins 2011.
130. Jo, S.; Lim, J. B.; Klauda, J. B.; Im, W. CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes. Biophys. J. 2009, 97, 50-58.
131. Jo, S.; Kim, T.; Im, W. Automated Builder and Database of Protein/Membrane Complexes for Molecular Dynamics Simulations. PLoS ONE 2007, 2, e880.
132. Mihailescu, M.; Vaswani, R. G.; Jardón-Valadez, E.; Castro-Román, F.; Freites, J. A.; Worcester, D. L.; Chamberlin, A. R.; Tobias, D. J.; White, S. H. Acyl-chain methyl distributions of liquid-ordered and -disordered membranes. Biophys. J. 2011, 100, 1455-1462.
133. Janosi, L.; Gorfe, A. Importance of the sphingosine base double-bond geometry for the structural and thermodynamic properties of sphingomyelin bilayers. Biophys. J. 2010, 99, 2957-2966.
134. Hall, A.; Róg, T.; Karttunen, M.; Vattulainen, I. Role of glycolipids in lipid rafts: a view through atomistic molecular dynamics simulations with galactosylceramide. J. Phys. Chem. B 2010, 114, 7797-7807.
135. de Meyer, F.; Smit, B. Effect of cholesterol on the structure of a phospholipid bilayer. Proc. Natl. Acad. Sci. M.S.A. 2009, 106, 3654-3658.
136. Róg, T.; Martinez-Seara, H.; Munck, N.; Oresic, M.; Karttunen, M.; Vattulainen, I. Role of cardiolipins in the inner mitochondrial membrane: insight gained through atom-scale simulations. J. Phys. Chem. B 2009, 113, 3413-3422.
137. Martinez-Seara, H.; Róg, T.; Pasenkiewicz-Gierula, M.; Vattulainen, I.; Karttunen, M.; Reigada, R. Interplay of unsaturated phospholipids and cholesterol in membranes: effect of the double-bond position. Biophys. J. 2008, 95, 3295-3305.
138. Bhide, S. Y.; Zhang, Z.; Berkowitz, M. L. Molecular Dynamics Simulations of SOPS and Sphingomyelin Bilayers Containing Cholesterol. Biophys J. 2007, 92, 1284-1295.
139. Cheng, M. H.; Liu, L. T.; Saladino, A. C.; Xu, Y.; Tang, P. Molecular dynamics simulations of ternary membrane mixture: phosphatidylcholine, phosphatidic acid, and cholesterol. J. Phys. Chem. B 2007, 111, 14186-14192.
140. Niemelä, P. S.; Ollila, S.; Hyvönen, M. T.; Karttunen, M.; Vattulainen, I. Assessing the nature of lipid raft membranes. PLoS Comput. Biol. 2007, 3, e34.
141. Niemelä, P. S.; Hyvönen, M. T.; Vattulainen, I. Atom-scale molecular interactions in lipid raft mixtures. Biochim. Biophys. Acta 2009, 1788, 122-135.
142. Zidar, J.; Merzel, F.; Hodoscek, M.; Rebolj, K.; Sepci, K.; Macek, P.; Janezic, D. Liquid-ordered phase formation in cholesterol/sphingomyelin bilayers: all-atom molecular dynamics simulations. J. Phys. Chem. B 2009, 113, 15795-15802.
143. Pandit, S. A.; Vasudevan, S.; Chiu, S. W.; Mashl, R. J.; Jakobsson, E.; Scott, H. L. Sphingomyelin-cholesterol domains in phospholipid membranes: atomistic simulation. Biophys. J. 2004, 87, 1092-1100.
144. Niemelä, P. S.; Hyvönen, M. T.; Vattulainen, I. Influence of chain length and unsaturation on sphingomyelin bilayers. Biophys. J. 2006, 90, 851-863.
145. Chiu, S. W.; Vasudevan, S.; Jakobsson, E.; Mashl, R. J.; Scott, H. L. Structure of sphingomyelin bilayers: a simulation study. Biophys. J. 2003, 85, 3624-3635.
146. Grossfield, A.; Feller, S. E.; Pitman, M. C. Convergence of molecular dynamics simulations of membrane proteins. Proteins 2007, 67, 31-40.
147. Bai, M. Dimerization of G-protein-coupled receptors: roles in signal transduction. Cell. Signal. 2004, 16, 175-186.
148. Milligan, G. G protein-coupled receptor dimerization: function and ligand pharmacology. Mol. Pharmacol. 2004, 66, 1-7.
149. Park, P. S.-.H.; Filipek, S.; Wells, J. W.; Palczewski, K. Oligomerization of G protein-coupled receptors: past, present, and future. Biochemistry 2004, 43, 15643-15656.
150. Terrillon, S.; Bouvier, M. Roles of G-protein-coupled receptor dimerization. EMBO Rep. 2004, 5, 30-34.
151. Fotiadis, D.; Jastrzebska, B.; Philippsen, A.; Müller, D. J.; Palczewski, K.; Engel, A. Structure of the rhodopsin dimer: a working model for G-proteincoupled receptors. Curr. Opin. Struct. Biol. 2006, 16, 252-259.
152. Javitch, J. A. The ants go marching two by two: oligomeric structure of Gprotein-coupled receptors. Mol. Pharmacol. 2004, 66, 1077-1082.
153. Filizola, M.; Weinstein, H. The structure and dynamics of GPCR oligomers: a new focus in models of cell-signaling mechanisms and drug design. Curr. Opin. Drug. Discov. Devel. 2005, 8, 577-584.
154. Kaczor, A. A.; Selent, J. Oligomerization of G protein-coupled receptors: biochemical and biophysical methods. Curr. Med. Chem. 2011, 18, 4606-4634.
155. Filipek, S.; Krzysko, K. A.; Fotiadis, D.; Liang, Y.; Saperstein, D. A.; Engel, A.; Palczewski, K. A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface. Photochem. Photobiol. Sci. 2004, 3, 628-638.
156. Teller, D. C.; Okada, T.; Behnke, C. A.; Palczewski, K.; Stenkamp, R. E. Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 2001, 40, 7761-7772.
157. Jastrzebska, B.; Maeda, T.; Zhu, L.; Fotiadis, D.; Filipek, S.; Engel, A.; Stenkamp, R. E.; Palczewski, K. Functional characterization of rhodopsin monomers and dimers in detergents. J. Biol. Chem. 2004, 279, 54663-54675.
158. Liang, Y.; Fotiadis, D.; Filipek, S.; Saperstein, D. A.; Palczewski, K.; Engel, A. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J. Biol. Chem. 2003, 278, 21655-21662.
159. Wu, B.; Chien, E. Y. T.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. M.; Cherezov, V.; Stevens, R. C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010, 330, 1066-1071.
160. Guixa-Gonzalez, R.; Bruno, A.; Marti-Solano, M.; Selent, J. Crosstalk within GPCR heteromers in schizophrenia and Parkinson's disease: physical or just functional? Curr. Med. Chem. 2012, 19, 1119-1134.
161. Waldhoer, M.; Fong, J.; Jones, R. M.; Lunzer, M. M.; Sharma, S. K.; Kostenis, E.; Portoghese, P. S.; Whistler, J. L. A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc. Natl. Acad. Sci. M.S.A. 2005, 102, 9050-9055.
162. Filizola, M.; Wang, S. X.; Weinstein, H. Dynamic models of G-protein coupled receptor dimers: indications of asymmetry in the rhodopsin dimer from molecular dynamics simulations in a POPC bilayer. J. Comput. Aided Mol. Des. 2006, 20, 405-416.
163. Allen, J. A.; Halverson-Tamboli, R. A.; Rasenick, M. M. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 2007, 8, 128-140.
164. Pike, L. J. Lipid Rafts Bringing Order to Chaos. J. Lipid Res. 2003, 44, 655-667.
165. Fallahi-Sichani, M.; Linderman, J. J. Lipid raft-mediated regulation of Gprotein coupled receptor signaling by ligands which influence receptor dimerization: a computational study. PLoS ONE 2009, 4, e6604.
166. Woolf, P. J.; Linderman, J. J. Self organization of membrane proteins via dimerization. Biophys. Chem. 2003, 104, 217-227.
167. Harroun, T. A.; Heller, W. T.; Weiss, T. M.; Yang, L.; Huang, H. W. Theoretical analysis of hydrophobic matching and membrane-mediated interactions in lipid bilayers containing gramicidin. Biophys. J. 1999, 76, 3176-3185.
168. Harroun, T. A.; Heller, W. T.; Weiss, T. M.; Yang, L.; Huang, H. W. Experimental evidence for hydrophobic matching and membrane-mediated interactions in lipid bilayers containing gramicidin. Biophys. J. 1999, 76, 937-945.
169. Weiss, T. M.; van der Wel, P. C. A.; Killian, J. A.; Koeppe, R. E., 2nd; Huang, H. W. Hydrophobic mismatch between helices and lipid bilayers. Biophys. J. 2003, 84, 379-385.
170. Crozier, P. S.; Stevens, M. J.; Woolf, T. B. How a small change in retinal leads to G-protein activation: initial events suggested by molecular dynamics calculations. Proteins 2007, 66, 559-574.
171. Sparr, E.; Ash, W. L.; Nazarov, P. V.; Rijkers, D. T. S.; Hemminga, M. A.; Tieleman, D. P.; Killian, J. A. Self-association of transmembrane alphahelices in model membranes: importance of helix orientation and role of hydrophobic mismatch. J. Biol. Chem. 2005, 280, 39324-39331.
172. Duque, D.; Li, X.; Katsov, K.; Schick, M. Molecular theory of hydrophobic mismatch between lipids and peptides. J. Chem. Phys. 2002, 116, 10478-10484.
173. Okada, T.; Fujiyoshi, Y.; Silow, M.; Navarro, J.; Landau, E. M.; Shichida, Y. Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography. Proc. Natl. Acad. Sci. M.S.A. 2002, 99, 5982-5987.
174. Park, J. H.; Scheerer, P.; Hofmann, K. P.; Choe, H. W.; Ernst, O. P. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 2008, 454, 183-187.
175. Selent, J.; Kaczor, A. A. Oligomerization of G protein-coupled receptors: computational methods. Curr. Med. Chem. 2011, 18, 4588-4605.
176. Filizola, M.; Olmea, O.; Weinstein, H. Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. Protein Eng. 2002, 15, 881-885.
177. Filizola, M.; Weinstein, H. The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics. FEBS J. 2005, 272, 2926-2938.
178. Filizola, M.; Weinstein, H. Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers. Biopolymers 2002, 66, 317-325.
179. Cordomí, A.; Perez, J. J. Structural rearrangements of rhodopsin subunits in a dimer complex: a molecular dynamics simulation study. J. Biomol. Struct. Dyn. 2009, 27, 127-147.
180. Provasi, D.; Johnston, J. M.; Filizola, M. Lessons from free energy simulations of delta-opioid receptor homodimers involving the fourth transmembrane helix. Biochemistry 2010, 49, 6771-6776.
181. Torney, D. C.; McConnell, H. M. Diffusion-Limited Reaction Rate Theory for Two-Dimensional Systems. Proc. R. Soc. Lond. A Math. Phys. Sci. 1983, 387, 147-170.
182. Johnston, J. M.; Wang, H.; Provasi, D.; Filizola, M. Assessing the relative stability of dimer interfaces in g protein-coupled receptors. PLoS Comput. Biol. 2012, 8, e1002649.
183. Periole, X.; Knepp, A. M.; Sakmar, T. P.; Marrink, S. J.; Huber, T. Structural determinants of the supramolecular organization of G protein-coupled receptors in bilayers. J. Am. Chem. Soc. 2012, 134, 10959-10965.
184. Khelashvili, G.; Albornoz, P. B. C.; Johner, N.; Mondal, S.; Caffrey, M.; Weinstein, H. Why GPCRs behave differently in cubic and lamellar lipidic mesophases. J. Am. Chem. Soc. 2012.
185. Grossfield, A.; Zuckerman, D. M. Quantifying uncertainty and sampling quality in biomolecular simulations. Annu. Rep. Comput. Chem. 2009, 5, 23-48.
186. Saulière-Nzeh Ndong, A.; Saulière-Nzeh, A. N.; Millot, C.; Corbani, M.; Mazères, S.; Lopez, A.; Salomé, L. Agonist-selective dynamic compartmentalization of human Mu opioid receptor as revealed by resolutive FRAP analysis. J. Biol. Chem. 2010, 285, 14514-14520.
187. Buch, I.; Harvey, M. J.; Giorgino, T.; Anderson, D. P.; De Fabritiis, G. Highthroughput all-atom molecular dynamics simulations using distributed computing. J. Chem. Inf. Model. 2010, 50, 397-403.
188. Harvey, M. J.; Giupponi, G.; Fabritiis, G. D. ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale. J. Chem. Theory Comput. 2009, 5, 1632-1639.
189. Shirts, M.; Pande, V. S. COMPUTING: Screen Savers of the World Unite! Science 2000, 290, 1903-1904.
190. Shaw, D. E.; Maragakis, P.; Lindorff-Larsen, K.; Piana, S.; Dror, R. O.; Eastwood, M. P.; Bank, J. A.; Jumper, J. M.; Salmon, J. K.; Shan, Y.; Wriggers, W. Atomic-level characterization of the structural dynamics of proteins. Science 2010, 330, 341-346.
191. Wang, W.; Donini, O.; Reyes, C. M.; Kollman, P. A. Biomolecular simulations: recent developments in force fields, simulations of enzyme catalysis, protein-ligand, protein-protein, and protein-nucleic acid noncovalent interactions. Annu. Rev. Biophys. Biomol. Struct. 2001, 30, 211-243.
192. Woo, H. J.; Roux, B. Calculation of absolute protein-ligand binding free energy from computer simulations. Proc. Natl. Acad. Sci. M.S.A. 2005, 102, 6825-6830.
193. Roux, B. The calculation of the potential of mean force using computer simulations. Comput. Phys. Commun. 1995, 91, 275-282.
194. Kumar, S.; Rosenberg, J. M.; Bouzida, D.; Swendsen, R. H.; Kollman, P. A. THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comput. Chem. 1992, 13, 1011-1021.
195. Laio, A.; Gervasio, F. L. Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science. Rep. Prog. Phys. 2008, 71, 126601.
196. Leone, V.; Marinelli, F.; Carloni, P.; Parrinello, M. Targeting biomolecular flexibility with metadynamics. Curr. Opin. Struct. Biol. 2010, 20, 148-154.
197. Buch, I.; Sadiq, S. K.; De Fabritiis, G. Optimized Potential of Mean Force Calculations for Standard Binding Free Energies. J. Chem. Theory Comput. 2011, 7, 1765-1772.
198. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 1983, 4, 187-217.
199. Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc. 1996, 118, 11225-11236.
200. Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput. 2008, 4, 435-447.
201. MacKerell; Bashford, D.; Bellott; Dunbrack; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E.; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiórkiewicz-Kuczera, J.; Yin, D.; Karplus, M. All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins†. J. Phys. Chem. B 1998, 102, 3586-3616.
202. Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kalé, L.; Schulten, K. Scalable molecular dynamics with NA.M.D. J. Comput. Chem. 2005, 26, 1781-1802.
203. MacKerell, A. D., Jr.; Banavali, N.; Foloppe, N. Development and current status of the CHARMM force field for nucleic acids. Biopolymers 2000, 56, 257-265.
204. Fitch, B. ; Germain, R. ; Mendell, M.; Pitera, J.; Pitman, M.; Rayshubskiy, A.; Sham, Y.; Suits, F.; Swope, W.; Ward, T. J. ; Zhestkov, Y.; Zhou, R. Blue Matter, an application framework for molecular simulation on Blue Gene. Journal of Parallel and Distributed Computing 2003, 63, 759-773.
205. Christen, M.; Hünenberger, P. H.; Bakowies, D.; Baron, R.; Bürgi, R.; Geerke, D. P.; Heinz, T. N.; Kastenholz, M. A.; Kräutler, V.; Oostenbrink, C.; Peter, C.; Trzesniak, D.; van Gunsteren, W. F. The GROMOS software for biomolecular simulation: GROMOS05. J. Comput. Chem. 2005, 26, 1719-1751.
206. Harvey, M. J.; Giupponi, G.; De Fabritiis, G. ACEMD: Accelerating biomolecular dynamics in the microsecond time-scale. J. Chem. Theory Comput. 2009, 5, 1632-1639
207. Wang, J.; Cieplak, P.; Kollman, P. A. How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J. Comput. Chem. 2000, 21, 1049-1074.
208. Bowers, K. J.; Chow, E.; Xu, H.; Dror, R. O.; Eastwood, M. P.; Gregersen, B. A.; Klepeis, J. L.; Kolossvary, I.; Moraes, M. A.; Sacerdoti, F. D.; Salmon, J. K.; Shan, Y.; Shaw, D. E. In: Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters, SC 2006 Conference, Proceedings of the ACM/IEEE on Supercomputing; 2006; pp. 43.