Local Conformational Preferences of Peptides Near Attached Cations: Structure Determination by First-Principles Theory and IR-Spectroscopy

Abstract

In the transition from secondary to tertiary structure in peptides and proteins, turns take a special role. They are the hinges that arrange the periodic secondary structure elements (helices and strands) to the native fold. It is a known effect that Li+ alters peptide backbone structure,[1] and we investigate this effect on the structure and dynamics of turns for model peptides Ac-Ala-Ala-Pro-Ala-NMe (AAPA) and Ac-Ala-Asp-Pro-Ala-NMe (ADPA) by theoretical conformational predictions and experimental vibrational spectroscopy. On theory side, accurate conformational predictions can not succeed without a trustworthy description of the potential energy surface, but standard force fields lack this detailed accuracy for the ion-peptide systems investigated. We show that accurate predictions can be achieved by a first-principles approach (van der Waals corrected density functional theory (DFT) in the PBE generalized gradient approximation[2]), and verify all our predictions by comparison to infrared spectroscopy in the same clean-room environment (spectra obtained in vacuo, using the FELIX free-electron laser facility).We predict canonical turn conformations for AAPA and ADPA alone. Li+ and Na+, by adsorbing to C=O groups, induce unusual backbone conformations and prevent H bond formation. We show that accounting for finite-temperature free energy contributions (harmonic approximation) is essential for a consistent comparison between theoretically predicted conformers and experimental spectra. The comparison suggests that multiple conformers coexist at finite temperature, based on theoretically derived spectra including anharmonic effects for individual conformers by ab initio Born-Oppenheimer molecular dynamics (MD) simulations. Intriguingly, some of the predicted low-energy conformers contribute less than others to the observed spectra. The same MD simulations give insights into backbone motion patterns like peptide bond crankshaft rotation.[1] Seebach et al. Modern Synthetic Methods 7, 1 (1995).[2] Tkatchenko, Scheffler, Phys. Rev. Lett. 102, 073005 (2009).