Abstract
The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last 15 years strongly suggest that amino acids residues display unique and restricted conformational preferences in the unfolded state of peptides and proteins, contrary to one of the basic assumptions of the canonical random coil model. To fully understand residue level order/disorder, however, one has to gain a quantitative, experimentally based picture of conformational distributions and to determine the physical basis underlying residue-level conformational biases. Here, we review the experimental, computational and bioinformatic evidence for conformational preferences of amino acid residues in (mostly short) peptides that can be utilized as suitable model systems for unfolded states of peptides and proteins. In this context particular attention is paid to the alleged high polyproline II preference of alanine. We discuss how these conformational propensities may be modulated by peptide solvent interactions and so called nearest-neighbor interactions. The relevance of conformational propensities for the protein folding problem and the understanding of IDPs is briefly discussed.
Highlights
Over the last few decades, one of the primary goals of protein research has been to more fully understand the driving forces behind protein folding, unfolding, and mis-folding [1,2,3,4,5,6]
Another point of contention with regard to the random coil model lies in the Isolated Pair Hypothesis” (IPH), i.e., the implicit assumption that conformational sampling of residues are considered independent of the properties and the conformation of their nearest-neighbors in the unfolded state
From this plot one infer two major sub-populations within the manifold of conformational families, namely one centered at = 160 which contains mainly extended -strand populations, and a second centered at = 70 which contains predominantly encompasses the canonical polyproline (pPII) as well as -turn-like conformations. These results suggest that the peptide exists in an ensemble of inter-converting structures, among which, pPII is only one of many conformations sampled by its alanine residues
Summary
Over the last few decades, one of the primary goals of protein research has been to more fully understand the driving forces behind protein folding, unfolding, and mis-folding [1,2,3,4,5,6]. In addition to discussing studies on non-alanine peptides, we briefly reflect on the current debate on the choice of model systems used for exploring these intrinsic conformational biases, through experimental means Taken altogether, these results suggest, that conformational ensembles for amino acid residues are varied, unique, and unexplainable in the context of pure steric interaction. These results suggest, that conformational ensembles for amino acid residues are varied, unique, and unexplainable in the context of pure steric interaction Another point of contention with regard to the random coil model lies in the IPH, i.e., the implicit assumption that conformational sampling of residues are considered independent of the properties and the conformation of their nearest-neighbors in the unfolded state.
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