Conformation Specific Spectroscopic Investigation of - and /-peptides:

Conformation Specific Spectroscopic Investigation of - and /-peptides:

Conformation Specific Spectroscopic Investigation of - and /-peptides: Insight Into The Amide I and Amide II Spectral Signatures RG07 William H. James III, Christian W. Mller, Esteban E. Baquero, and Timothy S. Zwier Purdue University, West Lafayette IN 47907 Soo Hyuk Choi and Samuel H. Gellman University of Wisconsin-Madison, Madison WI 53706 June 19, 2008 63rd OSU International Symposium on Molecular Spectroscopy What Questions Can We Answer? Linear and 2D IR Spectra of d(GC)8 Solution Phase and Conformation Specific Gas Phase IR Spectra of Ac-3-Phe-NHMe A.T. Krummel, M.T. Zanni J. Phys. Chem. B 110 13991 (2006) Conformation Specific Spectra Connect Experiment to Theory to Gain Insight into the Coupling of Modes of a Particular Structure. E. Baquero, et al., J. Am. Chem. Soc. 130 4784 (2008). What Can Be Learned From Our Methods? Resonant ion dip infrared spectroscopy (RIDIRS): Conformation specific IR spectrum Supersonic Expansion cools gas phase molecules to effective temperatures of a few degrees Kelvin B AD C CA E B BB A B A A B UV C D C E B* B B*C B* A A C B* Boltzmann distribution of the vibrational

population prior to expansion UV Source fixed: Provides l selectivity IR Source tuned AgGaSe2 crystal provides tunability form ~1000-1800 cm-1. Collisional cooling to zero-point vibrational level Mass selective, conformation specific IR spectroscopy. Peptide Containing Systems O O N H O N H O N H Ac-3-hPhe-NHMe N H Ac-3-hPhe-3-Ala-NHMe C8 and C6 O O N H N H E. Baquero et al., JACS 130 4795 (2008)

NH O NH O H N O Ac-ACPC-(D)-Phe-NHMe C7/C8 and C11 C7/C8 and C11 O O N H O Ac-ACPC-(L)-Phe-NHMe C5/C8 H N N H O Ac-3-hAla-(L)Phe-NHMe C7/C8, C5/C6, C7 O O N H H N N H O

Ac-Phe-ACPC-NHMe O NH O H N N H N H O N H C10, C6/C6, C8/C8, C6/C8 C10, C6/C6, C8/C8, C6/C8 O N H Ac-3-hAla-3-hPhe-NHMe E. Baquero et al., JACS 130 4784 (2008) O O O H N N H O Ac-3-hAla-(D)Phe-NHMe C7/C8, C11, C5/C6 H N

N H O H N O Ac-Phe- -hAla-NHMe 3 C5/C8,C7/C8, C11, C5/C6, C7/C11 The Simplest System C6 C6(a)(1) 0.00 kJ/mol O N H N H Ac-3-Phe-NHMe C6 C8 NH Stretch Spectral Region Proven to be Exceptionally Diagnostic! How Diagnostic Is the 1300-1800 cm-1 Region? Ion intensity (a.u.) O C6(b)(1) 5.86 kJ/mol C8 C8(b)(3) 8.66 kJ/mol C8(d)(3) 9.88 kJ/mol C8(a)(2) 10.05 kJ/mol 3350 3400 3450 -1 Wavenumber (cm )

Two Conformers Resolved. Firm Assignments Based on NH Stretch Spectral Region. 3500 B3LYP/6-31+G(D) Frequencies Scaled 0.96 B3LYP/6-31+G(D) Scaled 0.98 The Simplest System O O C6a(1) N H N H Ac-3-Phe-NHMe C6b(1) C6 C8 Very Similar Signatures in C=O Stretch Region NH Bend Appears to be Slightly More Diagnostic C8b(3) C8d(3) C8a(2) 1450 1500 1550 1600 1650 -1 Wavenumber (cm ) 1700 1750

NH bend shows increase in intensity for C6 ring, both experimentally and computationally. Diagnostic NH Bend: Is There A Trend? O C6 O N H N H Ac-3-hPhe-NHMe C8 OH O O N H C6 N H Ac-3-hTyr-NHMe 1400 1500 1600 -1 Wavenumber (cm ) 1700 Only one conformer observed for Ac-3-hTyr-NHMe, a C6. C=O Stretch and NH bend Similar to C6 of Ac-3-hPhe-NHMe. NH Bend Enhancement in C6 H-bonded Conformer. Ac-3-hPhe-3-Ala-NHMe O O O N H Ac-3-hAla-3-hPhe-NHMe O

N H N H N H C10 O O N H N H C6/C6 C6/C6 C10 C8/C8 unassigned 1450 1500 1550 1600 1650 -1 Wavenumber (cm ) 1700 1750 1450 1500 1550 1600 1650 -1 Wavenumber (cm ) 1700 Peptide Containing Systems O O

N H O N H O N H Ac-3-hPhe-NHMe N H Ac-3-hPhe-3-Ala-NHMe C8 and C6 O O N H N H E. Baquero et al., JACS 130 4795 (2008) NH O NH O H N O Ac-ACPC-(D)-Phe-NHMe C7/C8 and C11 C7/C8 and C11 O O N

H O Ac-ACPC-(L)-Phe-NHMe C5/C8 H N N H O Ac-3-hAla-(L)Phe-NHMe C7/C8, C5/C6, C7 O O N H H N N H O Ac-Phe-ACPC-NHMe O NH O H N N H N H O N H C10, C6/C6, C8/C8, C6/C8

C10, C6/C6, C8/C8, C6/C8 O N H Ac-3-hAla-3-hPhe-NHMe E. Baquero et al., JACS 130 4784 (2008) O O O H N N H O Ac-3-hAla-(D)Phe-NHMe C7/C8, C11, C5/C6 H N N H O H N O Ac-Phe- -hAla-NHMe 3 C5/C8,C7/C8, C11, C5/C6, C7/C11 O H N N H O H N

O Ac-Phe-3-hAla-NHMe C5/C8 A C5/C8b(1) C5/C8 C5/C6 B C5/C6a(1) C5/C6 1500 3300 3350 3400 3450 -1 Wavenumber (cm ) 3500 1550 1600 1650 -1 Wavenumber (cm ) Reasonable representation for C5/C6, but not for C5/C8 in NH Stretch Region. MID-IR Region Shows Much Better Agreement for C5/C8. 1700 O O N H N H O H N N H

O Ac- -hAla-(L)Phe-NHMe 3 O N H H N O Ac- -hAla-(D)Phe-NHMe 3 A (C7/C8) A' (C7/C8) C (C7/C8) B (C11) D (C7/C8) G (C5/C6) C' (C7/C8) 1400 1500 1600 -1 Wavenumber (cm ) 1700 1400 1500 1600 -1 Wavenumber (cm ) Conformation and Diastereomeric Specific Mid-IR Spectra 1700 C7/C8 Conformational Family O O N H

N H O H N O N H O Ac-3-hAla-(L)Phe-NHMe N H H N O Ac-3-hAla-(D)Phe-NHMe C7L/C8c(1) C7L/C8d(3) C7D/C8c(3) C7L/C8a(1) C7L/C8h(3) 1450 1450 1500 1550 1600 1650 1700 -1 Wavenumber (cm ) 1750 1500 1550 1600 1650 -1 Wavenumber (cm ) 1700

1750 Transition Dipole Coupling (TDC) Model A C7L/C8c(1) TDC does not accurately describe experimental spectra. C C7D/C8c(3) Poor description anticipated due to carbonyls being nearest neighbors and being covalently linked. D C7L/C8h(3) O O N H 1660 1680 1700 1720 -1 Wavenumber (cm ) B3LYP/6-31+G(D) Transition Dipole Coupling Model N H H N O Ac-3-hAla-(L)Phe-NHMe Transition Dipole Coupling (TDC) Model G C5/C6b(2) TDC does not accurately describe experimental spectra. Poor description anticipated due to carbonyls being nearest neighbors and being covalently linked. E C5/C6a(1) O

O N H 1640 1660 1680 1700-1 1720 Wavenumber (cm ) B3LYP/6-31+G(D) Transition Dipole Coupling Model N H H N O Ac-3-hAla-(L)Phe-NHMe -peptide Spectral Signatures C6 OH C8 O O O C6 C10 N H N H O N H N H C6/C6 C8/C8 O O

O N H N H N H C6/C6 C10 unassigned 1450 1500 1550 1600 1650 -1 Wavenumber (cm ) 1700 O O O N H N H N H Both Amide I and II Regions are Diagnostic! /-peptide Spectral Signatures C5/C8 C5/C6 O C7/C11 H N N H

H N O C7/C8 O C7/C8 O C7/C8 O N H C7/C8 H N N H O C5/C6 C7/C8 C11 O O N H C7/C8 H N N H O 1500 1550 1600 1650 1700 -1 Wavenumber (cm ) 1750 /-peptide Spectral Signatures

C5/C8 O O NH H N N H C7/C8 O C11 NH O C7/C8 O H N N H O C7/C8 O C7/C8 NH O H N N H O 1500 1550 1600 1650 1700 -1 Wavenumber (cm )

1750 Conclusions Resolved 26 Conformation Specific Spectra of 10 Peptide Containing Systems. Both C=O Stretch and NH Bend are fairly diagnostic. B3LYP/6-31+G(D) Computed Spectra are Modestly Representing Experimental Spectra Future Work Continue and Expand Coupling Analysis to Other Theoretical Methods. Record Spectral Signatures of Gamma Peptide Systems in the Amide I Region. Acknowledgements Professor Samuel H. Gellman Soo Hyuk Choi Professor Timothy S. Zwier Current Group Members: Dr. Christian Mller Dr. Mike Nix Tracy LeGreve Nathan Pillsbury Joshua Newby Chirantha Rodrigo Joshua Sebree Evan Buchanan Former Group Members: Dr. Jaime Stearns Dr. Talitha Selby Dr. Jasper Clarkson Dr. Ching-Ping Liu Dr. Esteban Baquero Dr. V. Alvin Shubert Professor Martin Zanni FUNDING Computational Resources

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