全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用：99美元
投递稿件

查看量下载量

相关文章

更多...
-  2018 


DOI: 10.3866/PKU.WHXB201706303

Full-Text   Cite this paper   Add to My Lib

Abstract:

Multi-scale quantum-mechanical/molecular-mechanical (QM/MM) and large-scale QM simulation provide valuable insight into enzyme mechanism and structure-property relationships. Analysis of the electron density afforded through these methods can enhance our understanding of how the enzyme environment modulates reactivity at the enzyme active site. From this perspective, tools from conceptual density functional theory to interrogate electron densities can provide added insight into enzyme function. We recently introduced the highly parallelizable Fukui shift analysis (FSA) method, which identifies how frontier states of an active site are altered by the presence of an additional QM residue to identify when QM treatment of a residue is essential as a result of quantum-mechanically affecting the behavior of the active site. We now demonstrate and analyze distance and residue dependence of Fukui function shifts in pairs of residues representing different non-covalent interactions. We also show how the interpretation of the Fukui function as a measure of relative nucleophilicity provides insight into enzymes that carry out SN2 methyl transfer. The FSA method represents a promising approach for the systematic, unbiased determination of quantum mechanical effects in enzymes and for other complex systems that necessitate multi-scale modeling.
Multi-scale quantum-mechanical/molecular-mechanical (QM/MM) and large-scale QM simulation provide valuable insight into enzyme mechanism and structure-property relationships. Analysis of the electron density afforded through these methods can enhance our understanding of how the enzyme environment modulates reactivity at the enzyme active site. From this perspective, tools from conceptual density functional theory to interrogate electron densities can provide added insight into enzyme function. We recently introduced the highly parallelizable Fukui shift analysis (FSA) method, which identifies how frontier states of an active site are altered by the presence of an additional QM residue to identify when QM treatment of a residue is essential as a result of quantum-mechanically affecting the behavior of the active site. We now demonstrate and analyze distance and residue dependence of Fukui function shifts in pairs of residues representing different non-covalent interactions. We also show how the interpretation of the Fukui function as a measure of relative nucleophilicity provides insight into enzymes that carry out SN2 methyl transfer. The FSA method represents a promising approach for the systematic, unbiased

 References

[1]  18 Hartman J. D. ; Neubauer T. J. ; Caulkins B. G. ; Mueller L. J. ; Beran G. J. J. Biomol. NMR 2015, 62, 327. doi: 10.1007/s10858-015-9947-2
[2]  20 Liao R. Z. ; Thiel W. J. Comput. Chem. 2013, 34, 2389. doi: 10.1002/jcc.23403
[3]  21 Sadeghian K. ; Flaig D. ; Blank I. D. ; Schneider S. ; Strasser R. ; Stathis D. ; Winnacker M. ; Carell T. ; Ochsenfeld C. Angew. Chem. Int. Ed. 2014, 53, 10044. doi: 10.1002/anie.201403334
[4]  24 Isborn C. M. ; Goetz A. W. ; Clark M. A. ; Walker R. C. ; Martinez T. J. J. Chem. Theory Comput. 2012, 8, 5092. doi: 10.1021/ct3006826
[5]  26 Harris T. V. ; Szilagyi R. K. J. Comput. Chem. 2016, 37, 1681. doi: 10.1002/jcc.24384
[6]  27 Karelina M. ; Kulik H. J. J. Chem. Theory Comput. 2017, 13, 563. doi: 10.1021/acs.jctc.6b01049
[7]  28 Morgenstern A. ; Jaszai M. ; Eberhart M. E. ; Alexandrova A. N. Chem. Sci. 2017. doi: 10.1039/C7SC01301A
[8]  29 Geerlings P. ; De Proft F. ; Langenaeker W. Chem. Rev. 2003, 103, 1793. doi: 10.1021/cr990029p
[9]  32 Faver J. ; Merz K. M. Jr. J. Chem. Theory Comput. 2010, 6, 548. doi: 10.1021/ct9005085
[10]  33 Fukushima K. ; Wada M. ; Sakurai M. Sakurai M...Proteins: Struct., Funct., Bioinf. 2008, 71, 1940. doi: 10.1002/prot.21865
[11]  34 Guerra C. F. ; Handgraaf J. W. ; Baerends E. J. ; Bickelhaupt F. M. J. Comput. Chem. 2004, 25, 189. doi: 10.1002/jcc.10351
[12]  35 Ufimtsev I. S. ; Martí ; nez T. J. J. Chem. Theory Comput. 2009, 5, 2619. doi: 10.1021/ct9003004
[13]  37 Rutherford K. ; Le Trong I. ; Stenkamp R. E. ; Parson W. W. J. Mol. Biol. 2008, 380, 120. doi: 10.1016/j.jmb.2008.04.040
[14]  45 Case, D.A.; Berryman, J. T.; Betz, R.M.; Cerutti, D.S., Cheatham, Ⅲ, D.S.; Darden, T.A.; Duke, R.E.; Giese, T.J., Gohlke, H.; Goetz, A.W.; et al., Amber 2015; University of California: San Francisco. 2015.
[15]  46 Maier J. A. ; Martinez C. ; Kasavajhala K. ; Wickstrom L. ; Hauser K. E. ; Simmerling C. J. Chem. Theory Comput. 2015, 11, 3696. doi: 10.1021/acs.jctc.5b00255
[16]  47 Hornak V. ; Abel R. ; Okur A. ; Strockbine B. ; Roitberg A. ; Simmerling C. Proteins: Struct., Funct., Bioinf. 2006, 65, 712. doi: 10.1002/prot.21123
[17]  48 Wang J. ; Wolf R. M. ; Caldwell J. W. ; Kollman P. A. ; Case D. A. J. Comput. Chem. 2004, 25, 1157. doi: 10.1002/jcc.20035
[18]  54 Dupradeau F.-Y. ; Pigache A. ; Zaffran T. ; Savineau C. ; Lelong R. ; Grivel N. ; Lelong D. ; Rosanski W. ; Cieplak P. Phys. Chem. Chem. Phys. 2010, 12, 7821. doi: 10.1039/C0CP00111B
[19]  55 Allné ; r O. ; Nilsson L. ; Villa A. J. Chem. Theory Comput. 2012, 8, 1493. doi: 10.1021/ct3000734
[20]  56 Jorgensen W. L. ; Chandrasekhar J. ; Madura J. D. ; Impey R. W. ; Klein M. L. J. Chem. Phys. 1983, 79, 926. doi: 10.1063/1.445869
[21]  57 Ryckaert J.-P. ; Ciccotti G. ; Berendsen H. J. C. J. Comput. Phys. 1977, 23, 327. doi: 10.1016/0021-9991(77)90098-5
[22]  58 Schrodinger, L. L. C. The PyMOL Molecular Graphics System, Version 1.7.4.3. 2010.
[23]  59 Rohrdanz M. A. ; Martins K. M. ; Herbert J. M. J. Chem. Phys. 2009, 130, 054112. doi: 10.1063/1.3073302
[24]  66 Woodard R. W. ; Tsai M. D. ; Floss H. G. ; Crooks P. A. ; Coward J. K. J. Biol. Chem. 1980, 255, 9124.
[25]  2 Bakowies D. ; Thiel W. J. Phys. Chem. 1996, 100, 10580. doi: 10.1021/jp9536514
[26]  4 Monard G. ; Merz K. M. Acc. Chem. Res. 1999, 32, 904. doi: 10.1021/ar970218z
[27]  5 Gao J. L. ; Truhlar D. G. Annu. Rev. Phys. Chem. 2002, 53, 467. doi: 10.1146/annurev.physchem.53.091301.150114
[28]  6 Rosta E. ; Klahn M. ; Warshel A. J. Phys. Chem. B 2006, 110, 2934. doi: 10.1021/jp057109j
[29]  9 Senn H. M. ; Thiel W. Angew. Chem. Int. Ed. 2009, 48, 1198. doi: 10.1002/anie.200802019
[30]  10 Thellamurege N. M. ; Hirao H. J. Phys. Chem. B 2014, 118, 2084. doi: 10.1021/jp412538n
[31]  12 Halgren T. A. ; Damm W. Curr. Opin. Struct. Biol. 2001, 11, 236. doi: 10.1016/S0959-440X(00)00196-2
[32]  19 Fox S. J. ; Pittock C. ; Fox T. ; Tautermann C. S. ; Malcolm N. ; Skylaris C. K. J. Chem. Phys. 2011, 135, 224107. doi: 10.1063/1.3665893
[33]  22 Kulik H. J. ; Zhang J. ; Klinman J. P. ; Martinez T. J. J. Phys. Chem. B 2016, 120, 11381. doi: 10.1021/acs.jpcb.6b07814
[34]  23 Solt I. ; Kulhanek P. ; Simon I. ; Winfield S. ; Payne M. C. ; Csanyi G. ; Fuxreiter M. J. Phys. Chem. B 2009, 113, 5728. doi: 10.1021/jp807277r
[35]  25 Vanpoucke D. E. ; Oláh J. ; De Proft F. ; Van Speybroeck V. ; Roos G. J. Chem. Inf. Model. 2015, 55, 564. doi: 10.1021/ci5006417
[36]  30 Parr R. G. ; Yang W. J. Am. Chem. Soc. 1984, 106, 4049. doi: 10.1021/ja00326a036
[37]  31 Yang W. ; Mortier W. J. J. Am. Chem. Soc. 1986, 108, 5708. doi: 10.1021/ja00279a008
[38]  36 Petachem. http://www.petachem.com. (accessed May 20, 2017).
[39]  38 Patra N. ; Ioannidis E. I. ; Kulik H. J. PloS One 2016, 11, e0161868. doi: 10.1371/journal.pone.0161868
[40]  39 Zhang J. ; Kulik H. J. ; Martinez T. J. ; Klinman J. P. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 7954. doi: 10.1073/pnas.1506792112
[41]  40 Griffith S. C. ; Sawaya M. R. ; Boutz D. R. ; Thapar N. ; Katz J. E. ; Clarke S. ; Yeates T. O. J. Mol. Biol. 2001, 313, 1103. doi: 10.1006/jmbi.2001.5095
[42]  41 Labahn, J.; Granzin, J.; Schluckebier, G.; Robinson, D. P.; Jack, W. E.; Schildkraut, I.; Saenger, W. Proc. Natl. Acad. Sci.U. S. A. 1994, 91, 10957.
[43]  42 Anandakrishnan R. ; Aguilar B. ; Onufriev A. V. Nucleic Acids Res. 2012, 40, W537. doi: 10.1093/nar/gks375
[44]  43 Gordon J. C. ; Myers J. B. ; Folta T. ; Shoja V. ; Heath L. S. ; Onufriev A. Nucleic Acids Res. 2005, 33, W368. doi: 10.1093/nar/gki464
[45]  44 Myers J. ; Grothaus G. ; Narayanan S. ; Onufriev A. Proteins: Struct., Funct., Bioinf. 2006, 63, 928. doi: 10.1002/prot.20922
[46]  49 Bayly C. I. ; Cieplak P. ; Cornell W. ; Kollman P. A. J. Phys. Chem. 1993, 97, 10269. doi: 10.1021/j100142a004
[47]  50 Gordon M. S. ; Schmidt M. W. Theory Appl. Comput. Chem.: First Forty Years 2005, 1167
[48]  51 Harihara P. C. ; Pople J. A. Theor Chim Acta 1973, 28, 213. doi: 10.1007/bf00533485
[49]  52 Wang, F.; Becker, J.-P.; Cieplak, P.; Dupradeau, F.-Y. R.E.D. Python: Object Oriented Programming for Amber Force Fields; Université De Picardie -Jules Verne: Sanford|Burnham Medical Research Institute, Nov. 2013. http://q4md-forcefieldtools.org/REDServer-Development/ (accessed 5/20/17).
[50]  53 Vanquelef E. ; Simon S. ; Marquant G. ; Garcia E. ; Klimerak G. ; Delepine J. C. ; Cieplak P. ; Dupradeau F.-Y. Nucleic Acids Res. 2011, 39, W511. doi: 10.1093/nar/gkr288
[51]  60 Becke A. D. J. Chem. Phys. 1993, 98, 5648. doi: 10.1063/1.464913
[52]  61 Stephens P. J. ; Devlin F. J. ; Chabalowski C. F. ; Frisch M. J. J. Phys. Chem. 1994, 98, 11623. doi: 10.1021/j100096a001
[53]  62 Lee C. ; Yang W. ; Parr R. G. Phys. Rev. B 1988, 37, 785. doi: 10.1103/PhysRevB.37.785
[54]  1 Field M. J. ; Bash P. A. ; Karplus M. J. Comput. Chem. 1990, 11, 700. doi: 10.1002/jcc.540110605
[55]  3 Mordasini T. Z. ; Thiel W. Chimia 1998, 52, 288.
[56]  7 Lin H. ; Truhlar D. Theor. Chem. Acc. 2007, 117, 185. doi: 10.1007/s00214-006-0143-z
[57]  8 Warshel A. ; Levitt M. J. Mol. Biol. 1976, 103, 227. doi: 10.1016/0022-2836(76)90311-9
[58]  11 Ponder J. W. ; Wu C. ; Ren P. ; Pande V. S. ; Chodera J. D. ; Schnieders M. J. ; Haque I. ; Mobley D. L. ; Lambrecht D. S. ; DiStasio R. A. Jr. J. Phys. Chem. B 2010, 114, 2549. doi: 10.1021/jp910674d
[59]  13 Vidossich P. ; Florin G. ; Alfonso-Prieto M. ; Derat E. ; Shaik S. ; Rovira C. J. Phys. Chem. B 2010, 114, 5161. doi: 10.1021/jp911170b
[60]  14 Carloni P. ; Rothlisberger U. ; Parrinello M. Acc. Chem. Res. 2002, 35, 455. doi: 10.1021/ar010018u
[61]  15 Kulik H. J. ; Luehr N. ; Ufimtsev I. S. ; Martinez T. J. J. Phys. Chem. B 2012, 116, 12501. doi: 10.1021/jp307741u
[62]  16 Liu F. ; Luehr N. ; Kulik H. J. ; Martí ; nez T. J. J.Chem. Theory Comput. 2015, 11, 3131. doi: 10.1021/acs.jctc.5b00370
[63]  17 Flaig D. ; Beer M. ; Ochsenfeld C. J. Chem. Theory Comput. 2012, 8, 2260. doi: 10.1021/ct300036s
[64]  63 Lu T. ; Chen F. J. Comput. Chem. 2012, 33, 580. doi: 10.1002/jcc.22885
[65]  64 Axelrod J. ; Tomchick R. J. Biol.Chem. 1958, 233, 702.
[66]  65 Hegazi M. F. ; Borchardt R. T. ; Schowen R. L. J. Am. Chem. Soc. 1979, 101, 4359. doi: 10.1021/ja00509a052

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133