Isotopically Edited Vibrational Spectra and Dynamics for Three-Strand B-Sheet Peptides. DFT Spectral and MD Dynamics Simulations

Peptide β-sheets are difficult for theoretical simulation, due to multiple forms and aggregation, but multi-strand hairpin models can have monomer structures with defined cross-strand anti-parallel H-bonding. Hairpins can be partially stabilized with selected turn sequences (e.g. DPro-Gly or Aib-Gly) or by incorporating aromatic cross-strand interactions. In three-stranded β-sheet models, the central strand is H-bonded to two others, possibly having a complex folding mechanism, depending on the balance of cross-strand and turn effects. We studied a series of 23-residue peptides having two turns composed of either DPro-Gly or Aib-Gly sequences and various cross-strand aromatic couplings. IR and VCD thermal equilibrium spectroscopic studies are supported by NMR-based structures and DFT modeling. MD dynamics simulations are correlated with IR-detected temperature-jump kinetics. These all have β-sheet structures, but differ in stabilities for different turns and aromatic contacts. DFT computations for an Ala-based structure with NMR constrained ϕ,ψ angles yield IR and VCD simulations consistent with experimental data. The structures are sharply twisted with the first hairpin being better formed. Aromatic stabilization was energetically effective for Trp-Tyr on strands 1-2, less on strands 2-3, but a similar sequence with no aromatic interactions formed better sheets. MD studies show bistable fluctuation in the DPro-Gly turns from Type 1’ to 2’, but Aib-Gly turns, with less torsional barrier, sampled more forms. These behaviors were evident in site-selected IR-detected T-jump relaxation kinetics. Isotopic labeling allows selected monitoring of turns and strands, and Aib-Gly have less spectral interference than DPro-Gly turns. Equilibrium IR as well as T-jump dynamics reflect higher stabilities for strand 1-2 interactions.