1. Structural Determination and Evaluation of Theoretical Models and Basis Sets of Cisplatin-Amino Acid Analogues by IRMPD Action Spectroscopy C.C. He, 1 X. Bao, 1 L. Hamlow, 1 Y. Zhu, 1 S. Strobehn, 1 B. Kimutai, 1 Y.-w. Nei, 1 G. Berden, 2 J. Gao, 2 J. Oomens, 2 C.S. Chow, 1 and M.T. Rodgers 1 * 1 Department of Chemistry, Wayne State University, Detroit, MI 48202 2 FELIX facility, Radboud University, 6525 ED Nijmegen, The Netherlands

2. Cisplatin [cis-diamminedichloroplatinum(II)] Anti-cancer drug Chemical probe for structural RNA Resistance, neurotoxicity … leaving groups carrier ligands Carrier ligands determine the adduct profile Purine N7 position; G > A Amino acids are great ligands Lippert, B. Cisplatin : Chemistry and Biochemistry of a Leading Anticancer Drug; Verlag Helvetica Chimica Acta ;Wiley-VCH:Zu ̈ rich Baik, M. H.; Friesner, R. A.; Lippard, S. J. J Am Chem Soc 2002, 124, 4495.

3. Cisplatin Amino-acid Derivatives Oplatin (neutral) (ornithine-linked cisplatin) Shows preference to A over G Proven at the nucleoside and structural RNA level When binding to adenosine, two different isomers have been observed Chow Group and Rodgers Group, unpublished data Dalla Via, L.; Gia, O.; Magno, S. M.; Dolmella, A.; Marton, D.; Di Noto, V. Inorg Chim Acta 2006, 359, 4197. Glyplatin (deprotonated) (glycine-linked cisplatin) Simplicity and less flexibility Low computational cost

4. Instrumentation IRMPD yield = (  I f )/( I p +  I f ) Polfer, N. C.; Oomens J., Phys. Chem. Phys. 2007, 9, 3804. Sample: ~1-7 mM Glyplatin dissolved in MeOH:H 2 O (50:50) no acid (Infrared Multiple Photon Dissociation) IRMPD Action Spectroscopy or OPO/OPA laser

5. IRMPD Mechanism Rapid intramolecular vibrational relaxation. Initially absorbed photon energy is distributed through the ion and is ready for the next photon absorption. The ion continues to absorb photons and redistribute that energy until the dissociation threshold is reached. IRMPD requires the absorption of tens to hundreds of photons Polfer, N. C.; Oomens J., Mass Spectrometry Reviews, 2009, 28, 468– 494.

6. Hybrid Basis Sets Density Functional Theory Methods  B3LYP, CAM-B3LYP, LC-ωPBE, PBE0, B3PW91, mPW1PW91,M06 Treatment of Platinum (Pt)  Effective Core Potential  All-Electron Basis Sets Basis Sets for non-Metal Atoms  Pople, def2, Dunning Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian, Inc., Wallingford CT, 2009. Paschoal, D.; Marcial, B. L.; Lopes, J. F.; De Almeida, W. B.; Dos Santos, H. F. J Comput Chem 2012, 33, 2292. de Berredo, R. C.; Jorge, F. E. J Mol Struc-Theochem 2010, 961, 107. de Berredo, R. C.; Jorge, F. E.; Jorge, S. S.; Centoducatte, R. Comput Theor Chem 2011, 965, 236. Malik, M.; Michalska, D. Spectrochim Acta A 2014, 125, 431. EMSL Basis Set Exchange https://bse.pnl.gov/bse/portal

7. Basis Set for non-Metal Atoms EMSL Basis Set Exchange https://bse.pnl.gov/bse/portal Gaussian 09 6-31Gdef2-SVPcc-pVDZ 6-31G(d)aug-cc-pVDZ 6-31+G(d) 6-31+G(d,p) 6-311+G(d,p)def2-TZVPcc-pVTZ 6-311++G(d,p)def2-TZVPPDaug-cc-pVTZ 6-311+(2d,2p) 6-311+(3df,3dp) def2-QZVP def2-QZVPPD cc-pVQZ aug-cc-pVQZ Popledef2 (Ahlrichs)Dunning Double Zeta Triple Zeta Quadruple Zeta

8. IRMPD Experiment for Glyplatin B3LYP/def2-TZVPPD Pt: def2 ECP(Effective Core Potential) Scaling Factor: 0.98/0.95 x 5

9. Basis Sets Evaluation for Glyplatin B3LYP/LANL2DZ/varying Pt:LANL2DZ ECP x 5

10. Conclusions Best result with the lowest cost: B3LYP/mDZP/def2-TZVP Selected based on structural information, not necessarily good for energetic description x 5

11. Sidechain Effects

12. Professor M. T. Rodgers Professor Christine Chow Rodgers group members Xun Bao and Bett Kimutai (Chow group) Dr. Cliff Frieler Dr. Jos Oomens, Dr. Giel Berden and Juehan Gao FELIX supporting staff CLIO User Facility staff National Science FoundationDepartment of Chemistry Acknowledgements WSU C&IT FELIX Facility CLIO User Facility

13. Introduction ribosomal RNA (rRNA): Protein synthesis Binding pockets  Good drug target  New drug binding site detection Crick, F. Nature 1970, 227, 561 Franceschi, F. Future Microbiol 2007, 2, 571 DNA replication transcription RNA translation protein

14. Treatment of Platinum(Pt) Basis Set with Effective Core Potential (ECP)  LANL2DZ, LANL2TZ, LANL2TZ(f)  SDD: works well for transition metals  def2: size consistent on all atoms All-electron Basis Set  DZP: accurate and still affordable  ADZP: provide more flexibility in the core region  mDZP: DZP + one set of d functions de Berredo, R. C.; Jorge, F. E. J Mol Struc-Theochem 2010, 961, 107. de Berredo, R. C.; Jorge, F. E.; Jorge, S. S.; Centoducatte, R. Comput Theor Chem 2011, 965, 236. Paschoal, D.; Marcial, B. L.; Lopes, J. F.; De Almeida, W. B.; Dos Santos, H. F. J Comput Chem 2012, 33, 2292. EMSL Basis Set Exchange https://bse.pnl.gov/bse/portal

15. Basis Sets Evaluation for Gplatin B3LYP/LANL2DZ/varying Pt:LANL2DZ ECP x 5

16. Basis Sets Evaluation for Gplatin B3LYP/LANL2DZ/varying Pt:LANL2DZ ECP x 5

17. Treatment Evaluation for Pt in Glyplatin B3LYP/Varying/def2-TZVP (Pt: corresponding ECP) x 5

18. Treatment Evaluation for Pt in Glyplatin Varying/LANL2DZ/def2-TZVP Pt: LanL2DZ ECP x 5

19. Validation trans-[PtCl(NH 3 ) 2 (H 2 O)] + Petris, A.; Ciavardini, A.; Coletti, C.; Re, N; Chiavarino, B; Crestoni, M. E.; Fornarini, S.;JPC Letters 2013, 4, 21, 3631-3635. B3LYP/LANL2TZ/cc-pVTZ SF:0.961

20. Validation cis-[PtCl(NH 3 ) 2 (H 2 O)] + Petris, A.; Ciavardini, A.; Coletti, C.; Re, N; Chiavarino, B; Crestoni, M. E.; Fornarini, S.;JPC Letters 2013, 4, 21, 3631-3635.

21. Supplementary