Randomizing the Unfolded State of Peptides (and Proteins) by Nearest Neighbor Interactions between Unlike Residues

Abstract

To explore the influence of nearest neighbors on conformational biases in unfolded peptides, we combined vibrational and 2D NMR spectroscopy to obtain the conformational distributions of selected "GxyG" host-guest peptides in aqueous solution: GDyG, GSyG, GxLG, GxVG, where x/y=A, K, L, V. Large changes of conformational propensities were observed due to nearest-neighbor interactions, at variance with the isolated pair hypothesis. We found that protonated aspartic acid and serine lose their above-the-average preference for turn-like structures in favor of polyproline II (pPII) populations in the presence of neighbors with bulky side chains. Such residues also decrease the above-the-average pPII preference of alanine. These observations suggest that the underlying mechanism involves a disruption of the hydration shell. Thermodynamic analysis of (3) J(H(N) ,H(α) ) (T) data for each x,y residue reveals that modest changes in the conformational ensemble masks larger changes of enthalpy and entropy governing the pPII↔β equilibrium indicating a significant residue dependent temperature dependence of the peptides' conformational ensembles. These results suggest that nearest-neighbor interactions between unlike residues act as conformational randomizers close to the enthalpy-entropy compensation temperature, eliminating intrinsic biases in favor of largely balanced pPII/β dominated ensembles at physiological temperatures.

Water-Mediated Electronic Structure of Oligopeptides Probed by Their UV Circular Dichroism, Absorption Spectra, and Time-Dependent DFT Calculations

“…However, over the last 15 years, experimental and computational studies have revealed that individual residues differ with regard to the conformational sampling, with the conformational entropy of short peptides and disordered and unfolded proteins being significantly less than assumed. [9][10][11][12][13][14][15][16][17] Recent results from MD and DFT computations have pointed to the same direction. [18][19][20][21][22][23][24] All residues predominantly sample the upper left quadrant of the Ramachandran plot, and they differ mostly in terms of their population of the polyproline II (pPII) (φ > -100 0 , ψ > 100 0 ) and β-strand region (φ ≤ -100 0 , ψ > 100 0 ).…”

Prediction of nearest neighbor effects on backbone torsion angles and NMR scalar coupling constants in disordered proteins

“…However, it was clear that effects of neighboring residues are not negligible, and a calibration using the increasingly growing library of values recorded for highly disordered systems, which permits the effect of nearest neighbors to be taken into account, provides a better reference for values representative of complete disorder . In order to gain mechanistic insights into the relation between nearest neighbors and ϕ/ψ distributions, the distribution of a given amino acid may be compared to that of the residue embedded in a sequence of Gly residues . The impact of nearest neighbors on 3 J HN‐Hα values, relative to Gly‐embedded residues, correlates reasonably well with nearest neighbor effects measured in a series of blocked dipeptides, with small systematic differences attributed to the effect of the adjacent blocking groups .…”

A new interpretation of the structure and solvent dependence of the far UV circular dichroism spectrum of short oligopeptides

“…2,5,7 The structure dependence of the delocalization of occupied orbitals invalidate Flory's isolated pair hypothesis, which are in line with experimental results. 23,24 The huge difference between the corresponding occupied MOs of GAG in implicit and explicit water strongly suggest that solvation energies of different residues are not additive.…”