Single-Conformation IR and UV Spectroscopy of a Prototypical Heterogeneous α/β Peptide: Is It a Mixed-Helix Former? Karl N. Blodgett1, Patrick S. Walsh1, Soo Hyuk Choi2, Timothy S. Zwier1 1Department of Chemistry, Purdue University 2Department of Chemistry, Yonsei University MI12 1

Why Study Foldamers? What is a foldamer? β,γ-amino acid incorporation Applications of β and α/β foldamers: β-peptide α/β-peptide 14-helix 12-helix 11-helix 14/15-helix Cholesteryl ester uptake inhibition Antimicrobial properties γ-secretase inhibition β α β α ACPC ACHC α Pro Secondary structure determination of new foldamers is important in potential applications Johnson, L.M., et al. Methods Enzymol, 2013, 523, 407-429 Horne, W.S., et al. Accounts of Chemical Research, 2008, 41, 1399-1408 2

Ac-Ala-β-ACHC-Ala-NHBn What are its Inherent Conformational Preferences? What are the inherent conformational preferences of a mixed α/β-peptide with a cyclically constraining cis-ACHC residue in the backbone? How do these structures compare with the crystal packing structure of its enantiomeric partner? Of its heptamer analogue? Dr. Soo Hyuk Choi Yonsei University Ac-Ala-β-ACHC-Ala-NHBn C9 Enantiomeric Partner C9 C11 C9 C11 Heptamer Analogue C11 C11 C9 Lee, M., et al., Angew. Chem. Int. Ed. 2013, 52, 12564-12567 3

Crystal Structure C9 C9 C11 μ=1.56 D C11 C9 C9 C11 C9 C11 C11 C9 C11 Lee, M., et al., Angew. Chem. Int. Ed. 2013, 52, 12564-12567 4

Experimental Methods MCP Turbo TOF Tube UV laser: 20 Hz IR laser: 10 Hz Dashed = Scanning Laser Solid = Fixed Laser 5

Computational Methods Ac-Ala-β-ACHC-Ala-NHBn Calculations performed at M052x/6-31+g(d) level of theory Calculations predict a complex potential energy landscape 17 structural families, 23 unique structures calculated ≤ 20 kJ/mol 6

Ac-Ala-β-ACHC-Ala-NHBn: UV Spectrum Ac-Ala-β-ACHC-Ala-NHBn 3 conformers present in the expansion 7

Ac-Ala-β-ACHC-Ala-NHBn, Conformer A: C7/C12/C8/C7 C7/C12/C8/C7 0.00 kJ/mol All amide groups involved in H-Bonding! C7 2.41 Å C7 C7 C8 1.89 Å C7 1.99 Å μ=1.45 D β-turn analogue former: d(Cα i, i+3) < 7 Å C12 2.05 Å C12 C8 8

Conformer A is a β-Turn Analogue Former C7/C12/C8/C7 0.00 kJ/mol μ=1.45 D 5.49 Å 9

Ac-Ala-β-ACHC-Ala-NHBn, Conformer B: C11/C9 Mixed Helix C11/C9 4.62 kJ/mol Right Handed Mixed Helix Former C11 C9 C9 μ=3.61 D C11 10

Conformer B vs. Enantiomeric Analogue Crystal Structure 11

Conformer B vs. Enantiomeric Analogue Crystal Structure 11

Conformer B vs. Enantiomeric Analogue Crystal Structure 11

Conformer B Replicates Mixed Helix Crystal Structure 11

Conformer B: Right Handed Helix Side Helical View Top-Down Helical View 12

Ac-Ala-β-ACHC-Ala-NHBn, Conformer C: C7/NH ● ● ● π/C11 C7/NH ● ● ● π/C11 1.37 kJ/mol “Cap Influenced” C7 1.99 Å C7 μ=3.66 D C11 1.97 Å π NH ● ● ● π C11 13

The Big Picture Conf B Conf C Conf A 14

Conclusions and Future Work C7/C12/C8/C7 β-Turn 0.00 kJ/mol μ=1.45 D Ac-Ala-β-ACHC-Ala-NHBn forms a β-turn analogue made of a tetramer H-bonded cycle 11/9 mixed helical structure is formed in both gas phase and crystal packing environment Future Work: Flip the Stereocenters: cis-ACHC chiral analogue, Solution phase and Crystal packing data show NO intramolecular H-bonding Extend the backbone: Ac-Ala-β-ACHC-Ala-β-ACHC-Ala-NHBn 11/9 Mixed Helix 4.62 kJ/mol μ=3.61 D 15

The Zwier Research Group: Acknowledgements The Zwier Research Group: Prof. Timothy Zwier Patrick S. Walsh Purdue University Joseph R. Gord Purdue University Dr. Soo Hyuk Choi Yonsei University 16