Protonation-induced stereoisomerism in nicotine: Conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics

Journal of Computer-Aided Molecular Design

Volumn 19, Issue 1, 2005, Pages 1-15

  Hammond, Philip S ^a   Wu, Yudong ^b,c   Harris, Rebecca ^a   Minehardt, Todd J ^d   Car, Roberto ^b   Schmitt, Jeffrey D ^a  

^a TARGACEPT INC   (United States)

^b PRINCETON UNIVERSITY   (United States)

^c HARVARD UNIVERSITY   (United States)

^d N Space Labs Inc   (United States)

Author keywords

ab initio molecular dynamics; AMBER; Car Parrinello; Nicotine; Nicotinic acetylcholine receptors; Protonation induced stereoisomerism

Indexed keywords

AMBER; CONFORMATIONS; ISOMERS; MOLECULAR DYNAMICS; MOLECULES; PROTONATION; STEREOCHEMISTRY;

AB INITIO; AB INITIO MOLECULAR DYNAMICS; ACETYLCHOLINE RECEPTOR; CAR-PARRINELLO; CONFORMATIONAL STUDY; DIASTEREOMERS; NICOTINIC ACETYLCHOLINE; NICOTINIC ACETYLCHOLINE RECEPTOR; PROTONATION-INDUCED STEREOISOMERISM; PROTONATIONS;

NICOTINE;

NICOTINE DERIVATIVE; NICOTINIC RECEPTOR;

ARTICLE; BINDING AFFINITY; COMPUTER PROGRAM; CONFORMATIONAL TRANSITION; DENSITY FUNCTIONAL THEORY; DIASTEREOISOMER; DRUG DESIGN; DRUG STRUCTURE; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; MOLECULAR MECHANICS; PRIORITY JOURNAL; PROTON TRANSPORT; STEREOISOMERISM;

EID: 20344385304     PISSN: 0920654X     EISSN: 15734951     Source Type: Journal    
DOI: 10.1007/s10822-005-0096-7     Document Type: Article

References (53)

1. M. Bencherif J.D. Schmitt 2002 Curr. Drug Target CNS. Neurol. Disord., 1 349
2. R.B. Barlow J.A.K. Howard O. Johnson 1986 Acta Crystallogr. Section C: Cryst. Struct. Commun. C42 85310.1107/S0108270186094301 1:CAS:528:DyaL28XltVKit7s%3D
3. C.H. Koo H.S. Kim 1965 Taehan Hwahakhoe Chi 9 134 1:CAS:528:DyaF28XktlCmu7k%3D
4. K.R. Chynoweth B. Ternai L.S. Simeral G.E. Maciel 1973 Mol. Pharmacol. 9 144 1:CAS:528:DyaE3sXhtlGmsLg%3D 4711697
5. J.F. Whidby J.I. Seeman 1976 J. Org. Chem. 41 1585 10.1021/jo00871a022 1:CAS:528:DyaE28Xhsl2ms7k%3D 1263010
6. D.E. Elmore D.A. Dougherty 2000 J. Org. Chem. 65 74210.1021/jo991383q 1:CAS:528:DC%2BD3cXksFymtA%3D%3D 10814006
7. H. Gohlke S. Schwarz D. Gundisch M.C. Tilotta A. Weber T. Wegge G. Seitz 2003 J. Med. Chem. 46 203 110.1021/jm020859m 1:CAS:528:DC%2BD3sXjt1amtbg%3D 12747776
8. S.J. Teague 2003 Nat. Rev. Drug. Discov. 2 527 10.1038/nrd1129 1:CAS:528:DC%2BD3sXltVaktrs%3D 12838268
9. C. Mattos D. Ringe 1993 Multiple Binding Modes. In: H. Kubinyi (Ed) 3D QSAR in Drug Design: Theory Methods and Applications Kluwer Academic Publishers Dordrecht 226-254
10. N. Zacharias D.A. Dougherty 2002 Trends Pharmacol. Sci. 23 281 10.1016/ S0165-6147(02)02027-8 1:CAS:528:DC%2BD38XkslGgtbw%3D 12084634
11. J.P.D.D.A. Gallivan 2000 J. Am. Chem. Soc. 122 870 10.1021/ja991755c 1:CAS:528:DC%2BD3cXltVyitg%3D%3D
12. J.D. Schmitt C.G. Sharples W.S. Caldwell 1999 J. Med. Chem. 42 3066 10.1021/jm990093z 1:CAS:528:DyaK1MXksFGhsrg%3D 10447950
13. D.A. Dougherty 1996 Science 271 163 1:CAS:528:DyaK28XktFOlsw%3D%3D 8539615
14. J.C. Ma D.A. Dougherty 1997 Chem. Rev. 97 1303 10.1021/cr9603744 1:CAS:528:DyaK2sXksV2kurk%3D 11851453
15. N. Zacharias D.A. Dougherty 2002 Trends Pharmacol. Sci. 23 281 10.1016/ S0165-6147(02)02027-8 1:CAS:528:DC%2BD38XkslGgtbw%3D 12084634
16. P.K. Weiner P.A. Kollman 1981 J. Comput. Chem. 2 287 10.1002/ jcc.540020311 1:CAS:528:DyaL3MXltFCltLs%3D
17. D.A. Case D.A. Pearlman J.W. Caldwell T.E. Cheatham III J. Wang W.S. Ross C.L. Simmerling T.A. Darden K.M. Merz R.V. Stanton A.L. Cheng J.J. Vincent M. Crowley V. Tsui H. Gohlke R.J. Radmer Y. Duan J. Pitera I. Massova G.L. Seibel U.C. Singh P.K. Weiner P.A. Kollman 2002 Amber[7] University of California San Francisco, CA
18. D.A. Pearlman D.A. Case J.W. Caldwell W.S. Ross T.E. Cheatham III S. DeBolt D. Ferguson G. Seibel P. Kollman 1995 Comput. Phys. Commun. 91 1-3 110.1016/0010-4655(95)00041-D 1:CAS:528:DyaK2MXps1Wrtrw%3D
19. R. Car M. Parrinell 1985 Phys. Rev. Lett. 55 2471 10.1103/ PhysRevLett.55.2471 1:CAS:528:DyaL28XhtVOlug%3D%3D 10032153
20. M. Sulpizi A. Laio J. VandeVondele A. Cattaneo U. Rothlisberger P. Carloni 2003 Proteins 52 212 10.1002/prot.10275 1:CAS:528:DC%2BD3sXlsFahtL4%3D 12833545
21. T.J. Minehardt N. Marzari R. Cooke E. Pate P.A. Kollman R. Car 2002 Biophys. J. 82 660 1:CAS:528:DC%2BD38XovVChsw%3D%3D 11806909
22. P. Carloni U. Rothlisberger M. Parrinello 2002 Acc. Chem. Res. 35 6 455 10.1021/ar010018u 1:CAS:528:DC%2BD38Xjs1Sgtbk%3D 12069631
23. J.S. Tse 2002 Annu. Rev. Phys. Chem. 53 24910.1146/ annurev.physchem.53.090401.105737 1:CAS:528:DC%2BD38Xks1Ois7s%3D 11972009
24. R. Car 2002 Quant. Struct.-Act. Relat. 21 2 9710.1002/ 1521-3838(200207)21:2<97::AID-QSAR97>3.0.CO;2-6 1:CAS:528:DC%2BD38XmtVektr8%3D
25. P. Hohenberg W. Kohn 1964 Phys. Rev. 136 B86410.1103/PhysRev.136.B864
26. W. Kohn L. Sham 1965 Phys. Rev. 140 A113310.1103/PhysRev.140.A1133
27. Sybyl Molecular Modeling Software [Version 6.9] 2003. Tripos, Inc., St. Louis, MO, USA
28. Z. Li H.A. Scheraga 1987 Proc. Natl. Acad. Sci. USA 84 66111:CAS:528:DyaL1cXlt1emuw%3D%3D 3477791
29. G. Chang W.C. Guida W.C. Still 1989 J. Am. Chem. Soc. 111 437910.1021/ ja00194a035 1:CAS:528:DyaL1MXitlSrsLo%3D
30. M. Saunders 1987 J. Am. Chem. Soc. 109 315010.1021/ja00244a051 1:CAS:528:DyaL2sXktVKmt7g%3D
31. M. Saunders K.N. Houk Y.D. Wu W.C. Still M. Lipton G. Chang W.C. Guida 1990 J. Am. Chem. Soc. 112 141910.1021/ja00160a020 1:CAS:528:DyaK3cXns1Sguw%3D%3D
32. D.A. Case D.A. Pearlman J.W. Caldwell T.E. Cheatham III J. Wang W.S. Ross C.L. Simmerling T.A. Darden K.M. Merz R.V. Stanton A.L. Cheng J.J. Vincent M. Crowley V. Tsui H. Gohlke R.J. Radmer Y. Duan J. Pitera I. Massova G.L. Seibel U.C. Singh P.K. Weiner P.A. Kollman 2002 Amber[7] University of California San Francisco, CA
33. W.D. Cornell P. Cieplak C.I. Bayly I.R. Gould K.M. Merz Jr D.M. Ferguson D.C. Spellmeyer T. Fox J.W. Caldwell P.A. Kollman 1995 J. Am. Chem. Soc. 117 517910.1021/ja00124a002 1:CAS:528:DyaK2MXlsFertrc%3D
34. C.I. Bayly P. Cieplak W. Cornell P.A. Kollman 1993 J. Phys. Chem. 97 1026910.1021/j100142a004 1:CAS:528:DyaK3sXlvVyqsLs%3D
35. M.J. Frisch G.W. Trucks H.B. Schlegel G.E. Scuseria M.A. Robb J.R. Cheeseman V.G. Zakrzewski J.A. Montgomery R.E. Stratmann J.C. Burant S. Dapprich J.M. Millam A.D. Daniels K.N. Kudin M.C. Strain O. Farkas J. Tomasi V. Barone M. Cossi R. Cammi B. Mennucci C. Pomelli C. Adamo S. Clifford J. Ochterski G.A. Petersson P.Y. Ayala Q. Cui K. Morokuma D.K. Malick A.D. Rabuck K. Raghavachari J.B. Foresman J. Cioslowski J.V. Ortiz B.B. Stefanov G. Liu A. Liashenko P. Piskorz I. Komaromi R. Gomperts R.L. Martin D.J. Fox T. Keith M.A. Al-Laham C.Y. Peng A. Nanayakkara C. Gonzalez M. Challacombe P.M.W. Gill B.G. Johnson W. Chen M.W. Wong J.L. Andres M. Head-Gordon E.S. Replogle J.A. Pople 1998 Gaussian 98 (Revision A1) Gaussian Inc, Pittsburgh, PA
36. T.J. Minehardt R. Cooke E. Pate P.A. Kollman 2001 Biophys. J. 80 11511:CAS:528:DC%2BD3MXkvFCjtrg%3D 11222280
37. Wang J., Wang W., Kollman P.A. (2001). Antechamber: An Accessory Software Package for Molecular Mechanical Calculations. Abstracts of Papers, 222nd ACS National Meeting, Chicago, IL, USA, August 26-30, 2001, COMP-135
38. H.J.C. Berendsen J.P.M. Postma W.F. Van Gunsteren A. DiNola J.R. Haak 1984 J. Chem. Phys. 81 368410.1063/1.448118 1:CAS:528:DyaL2cXmtlGksbY%3D
39. A.D. Becke 1993 J. Chem. Phys. 98 56481:CAS:528:DyaK3sXisVWgtrw%3D
40. J.P. Perdew J.A. Chevary S.H. Vosko K.A. Jackson M.R. Pederson D.J. Singh C. Fiolhais 1992 Phys. Rev. B: Condensed Matter 46 66711:CAS:528:DyaK38XlvFyks7c%3D
41. J. Perdew W. Yang 1992 Phys. Rev. B 45 1324410.1103/PhysRevB.45.13244
42. K. Laasonen A. Pasquarello R. Car C. Lee D. Vanderbilt 1993 Phys. Rev. B: Condensed Matter Mater Phys. 47 101421:CAS:528:DyaK3sXktlCmsLk%3D
43. P. Giannozzi F. De Angelis R. Car 2004 J. Chem. Phys. 120 13 590310.1063/ 1.1652017 1:CAS:528:DC%2BD2cXitlKqsL0%3D 15267472
44. J.P. Perdew K. Burke M. Ernzerhof 1996 Phys. Rev. Lett. 77 38651:CAS:528:DyaK28XmsVCgsbs%3D 10062328
45. S. Nose 1991 Prog. Theor. Phys. Suppl. 103 11:CAS:528:DyaK38XmslelsA%3D%3D
46. L.L.C. Schrodinger 2004 Jaguar Version 4.1 Portland OR, USA
47. Values for the 7 torsion angles listed in Figure 1, as well as the distance from the pyridine nitrogen to the cationic center nitrogen (N1-N8), N1-NH distance and the height above the plane of the pyridine ring of the cationic center nitrogen are also provided. Note that low-energy conformations were identified that correspond to those examined by Elmore and Dougherty (Ref. 6). A1 (cis 7) corresponds to cis +A from that paper, while B1(cis 11), A1(trans 3) and B1(trans 1) correspond to cis +B, trans +A and trans +B, repectively
48. Using Jaguar, full minimization at the DFT level (6-311G**) followed by further refinement (HF, CC-PVTZ(-f)) of all MM cis and trans nicotine conformations gave similar conformations to those found-by MM, but with a somewhat more limited range for the inter-ring torsion angle. An exhaustive search at the DFT level would have likely shown additional conformations
49. For aiMD trajectories carried out on protonated cis nicotine at 300 K (starting with cis A3), the conformation with the lowest energy (cis A1) was not found during 10 ps of dynamics. This implies a relatively large energy barrier between cis A1 and cis A3, making MD at elevated temperature necessary to thoroughly sample conformational space for the pyrrolidine ring
50. It is of note that in a similar random search on cis nicotine, but using the MMFF force field27, A7 and B7 were also identified as the highest energy conformations of those found
51. J.D. Schmitt 2000 Curr. Med. Chem. 7 7491:CAS:528:DC%2BD3cXltVGitLg%3D 10828287
52. Schutte Ch., Cordes F., On Dynamical Transitions Between Conformational Ensembles. Molecular Dynamics on Parallel Computers, Workshop, Juelich, Feb. 8-10, 1999, pp. 32-45. 2000
53. A. Fischer F. Cordes C. Schutte 1999 Comput. Phys. Commun. 37 121-122