How Cations Change Peptide Structure

Abstract

Specific interactions between cations and proteins have a strong impact on peptide and protein structure. Herein, we shed light on the nature of the underlying interactions, especially regarding effects on the polyamide backbone structure. This was done by comparing the conformational ensembles of model peptides in isolation and in the presence of either Li(+) or Na(+) by using state-of-the-art density-functional theory (including van der Waals effects) and gas-phase infrared spectroscopy. These monovalent cations have a drastic effect on the local backbone conformation of turn-forming peptides, by disruption of the hydrogen-bonding networks, thus resulting in severe distortion of the backbone conformations. In fact, Li(+) and Na(+) can even have different conformational effects on the same peptide. We also assess the predictive power of current approximate density functionals for peptide-cation systems and compare to results with those of established protein force fields as well as high-level quantum chemistry calculations (CCSD(T)).

Trends for isolated amino acids and dipeptides: Conformation, divalent ion binding, and remarkable similarity of binding to calcium and lead

“…The cation is bound to the two backbone oxygens and thus closes an otherwise incomplete 7-membered pseudocycle (iC 7 ). Similar structures were observed before by simulation and experiment for the interaction of sodium cations with small model peptides14. The side chain ‘ R ’ is oriented parallel to the axis (“axial”) of this pseudocycle and is hence referred to as .…”

“…The total number of conformers covered is 45,730. This is close to the limit of what can be accomplished computationally for a conformational search of this extent and for the extensively benchmarked1113141516171819 level of theory used to create the database (density-functional theory (DFT) based on a van-der Waals corrected generalized gradient functional (PBE + vdW)202122, see Methods).…”

“…The reliability of PBE + vdW for the peptide structure problem has been established by (i) comparisons to CCSD(T) benchmark investigations for oligo-alanine systems13 and alanine dipeptides with Li +  14, (ii) comparison to carefully performed basis-set extrapolated MP2 calculations11, and comparisons to experimental spectroscopic benchmarks15. Importantly, the actual conformations identified by PBE+vdW remain meaningful even in cases where, for larger oligopeptides, more expensive higher levels of theory are needed to reproduce small energetic differences to the exact conformational energy hierarchy found in experiment16171819.…”

Photodissociation of Conformer-Selected Ubiquitin Ions Reveals Site-Specific Cis/Trans Isomerization of Proline Peptide Bonds

“…39 Furthermore, we have recently demonstrated how cis/trans isomerization is influenced by interactions with mono-valent ciations. 40 The observation of two (or more) peaks in an ATD means that two (or more) different conformations with different cross sections are stable in the gas phase and do not interconvert on a ms time scale at 300 K. This implies that rather large free energy barriers separate their corresponding conformational space. A large number of hydrogen bonds that need to be broken simultaneously in order to change conformation could give rise to such a barrier.…”

How mono-valent cations bend peptide turns and a first-principles database of amino acids and dipeptides

“…In comparison to high-level quantum chemistry, the here used DFT methods give better than chemical accuracy; the FFs apparently fail to describe the subtleties of the cation peptide interactions. We show here how cation-peptide interactions can substantially change the backbone structure of a (bio)polymer [4]. The implications of the findings discussed here are not limited to the gas-phase.…”