How do Nearest-Neighbor Interactions Effect the Conformational Distributions in Peptides?

Abstract

For structural predictions of intrinsically disordered proteins (IDPs), knowledge about intrinsic propensities of amino acids must be complimented by information on nearest-neighbor interactions. To explore the influence of nearest-neighbors on conformational distributions of amino acid residues, we preformed a joint vibrational and 2D-NMR study of selected GxyG host-guest peptides: GDyG, GSyG, GxLG, GxVG, where x/y={A,K,LV}. The choice of D and S (L/V) for the x (y) position was motivated by their documented ability to drastically change the distribution of alanine in xAy tripeptide sequences in truncated coil libraries. Five J-coupling constants and amide I’ profiles of the respective IR, polarized Raman and Vibrational Circular Dichroism spectra were analyzed using a superposition of 2D-Gaussian functions in Ramachandran space representing sub-ensembles of pPII-, β-strand-, helical-, and turn-like conformations. Our analysis of the amide I' profiles exploits excitonic coupling between the local amide I′ modes in the tetra-peptides. Our results reveal that D and S particularly alter the conformation of their downstream neighbor. In a recent study, these amino acids were shown to have an unusually high preference for type I’/IIβ and asx-turns. A direct comparison of the ensemble obtained for serine in GSAG, GSLG and GSG reveals that A and L cause the asx-turn population to be mitigated in favor of more extended pPII/ β structures. Upon insertion of these ‘turn-forming’ residues, alanine's conformational ensemble is modestly changed (shift from pPII to β), while the position of pPII and particularly of β is shifted to lower ψ-values. DFT calculations indeed show that the forced reduction in ψ for A increases the H-bond distance for serine in the asx-turn conformation. Taken together, our results indicate that Dx and Sx-motifs might act as conformational randomizers in proteins, attenuating intrinsic propensities of neighboring residues.