Unfolded Peptides Research Articles

Different Degrees of Disorder in Long Disordered Peptides Can Be Discriminated by Vibrational Spectroscopy

The isotropic Raman, anisotropic Raman, IR, and vibrational circular dichroism (VCD) amide I profiles of a 20 residue homopeptide were calculated for different conformational mixtures that one would generally characterize as random coil or disordered. We first show that (1) pure polyproline II (pPII) coils, (2) statistical coils with different fractions pPII, β-strand, and right-handed helical residue conformations, and (3) ideal random coils (nearly equal probabilities for pPII, β, and right-handed helical) can be discriminated based on their respective VCD signal and, to a more limited extent, by means of the peak positions and asymmetries of the corresponding IR and Raman bands. Since molecular dynamics (MD) simulations of unfolded peptides (e.g., Aβ-segments) suggest a mixture of statistical coil and temporarily folded conformations, we calculated the amide I profiles of such mixtures composed of helical, β-strand, and disordered conformers and show that they give rise to rather distinct amide I profiles. Mixtures of regular structures with statistical coil segments can be discriminated from pure statistical and random coils by the amplitude of the negative amide I couplet in the VCD spectrum. We finally demonstrate the usefulness of such simulations by applying them to monomeric state of salmon calcitonin and the amyloid β fragment Aβ1-28, for which NMR data provide evidence for a coexistence between statistical coil and helical conformations. Altogether, our results show that the combined use of the four amide I profiles provides spectroscopists with a powerful tool to discriminate between different conformational manifolds that long unfolded and disordered peptides and proteins might adopt in solution.

PH-Independence of Trialanine and the Effects of Termini Blocking in Short Peptides: A Combined Vibrational, NMR, UVCD, and Molecular Dynamics Study

Several lines of evidence now well establish that unfolded peptides in general, and alanine in specific, have an intrinsic preference for the polyproline II (pPII) conformation. Investigation of local order in the unfolded state is, however, complicated by experimental limitations and the inherent dynamics of the system, which has in some cases yielded inconsistent results from different types of experiments. One method of studying these systems is the use of short model peptides, and specifically short alanine peptides, known for predominantly sampling pPII structure in aqueous solution. Recently, He et al. ( J. Am. Chem. Soc. 2012 , 134 , 1571 - 1576 ) proposed that unblocked tripeptides may not be suitable models for studying conformational propensities in unfolded peptides due to the presence of end effect, that is, electrostatic interactions between investigated amino acid residues and terminal charges. To determine whether changing the protonation states of the N- and C-termini influence the conformational manifold of the central amino acid residue in tripeptides, we have examined the pH-dependence of unblocked trialanine and the conformational preferences of alanine in the alanine dipeptide. To this end, we measured and globally analyzed amide I' band profiles and NMR J-coupling constants. We described conformational distributions as the superposition of two-dimensional Gaussian distributions assignable to specific subspaces of the Ramachandran plot. Results show that the conformational ensemble of trialanine as a whole, and the pPII content (χpPII = 0.84) in particular, remains practically unaffected by changing the protonation state. We found that compared to trialanine, the alanine dipeptide has slightly lower pPII content (χpPII = 0.74) and an ensemble more reminiscent of the unblocked Gly-Ala-Gly model peptide. In addition, a two-state thermodynamic analysis of the conformational sensitive Δε(T) and (3)J(H(N)H(α))(T) data obtained from electronic circular dichroism and H NMR spectra indicate that the free energy landscape of trialanine is similar in all protonation states. MD simulations for the investigated peptides corroborate this notion and show further that the hydration shell around unblocked trialanine is unaffected by the protonation/deprotonation of the C-terminal group. In contrast, the alanine dipeptide shows a reduced water density around the central residue as well as a less ordered hydration shell, which decreases the pPII propensity and reduces the lifetime of sampled conformations.

Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. II. Tripeptides with short side chains populating asx and β‐type like turn conformations

In the preceding paper, we found that ensembles of tripeptides with long or bulky chains can include up to 20% of various turns. Here, we determine the structural and thermodynamic characteristics of GxG peptides with short polar and/or ionizable central residues (D, N, C), whose conformational distributions exhibit higher than average percentage (>20%) of turn conformations. To probe the side-chain conformations of these peptides, we determined the (3)J(H(α),H(β)) coupling constants and derived the population of three rotamers with χ1 -angles of -60°, 180° and 60°, which were correlated with residue propensities by DFT-calculations. For protonated GDG, the rotamer distribution provides additional evidence for asx-turns. A comparison of vibrational spectra and NMR coupling constants of protonated GDG, ionized GDG, and the protonated aspartic acid dipeptide revealed that side chain protonation increases the pPII content at the expense of turn populations. The charged terminal groups, however, have negligible influence on the conformational properties of the central residue. Like protonated GDG, cationic GCG samples asx-turns to a significant extent. The temperature dependence of the UVCD spectra and (3)J(H(N)H(α)) constants suggest that the turn populations of GDG and GNG are practically temperature-independent, indicating enthalpic and entropic stabilization. The temperature-independent J-coupling and UVCD spectra of GNG require a three-state model. Our results indicate that short side chains with hydrogen bonding capability in GxG segments of proteins may serve as hinge regions for establishing compact structures of unfolded proteins and peptides.

Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. I. Tripeptides with long and predominantly hydrophobic side chains

We performed a conformational analysis of the central residues of three tripeptides glycyl-L-isoleucyl-glycine (GIG), glycyl-L-tyrosyl-glycine (GYG) and glycyl-L-arginyl-glycine (GRG) in aqueous solution, based on a global analysis of amide I' band profiles and NMR J-coupling constants. The results are compared with recently reported distributions of GVG, GFG and GEG. For GIG and GYG, we found that even though the polyproline II (pPII) fraction is below 0.5, it is still the most populated conformation, whereas GVG and GFG show both a larger β-strand fraction. For GRG, we observed a clear dominance of pPII over β-strand, reminiscent of observations for GEG and GKG. This finding indicates that terminal charges on otherwise hydrophobic residue side chains stabilize pPII over β-strand conformations. For all peptides investigated we found that a variety of compact and turn-like conformations constitute nearly 20 percent of their conformational distributions. Attempts to analyze our data with a simple two-state pPII-->/<--β model therefore do not yield any satisfactory reproduction of experimental results. A comparison of the obtained GxG ensembles with conformational distributions of GxG segments in truncated coil libraries (helices and sheets omitted) revealed a much larger fraction of type II β(i+2) and type III β like conformations for the latter. Thus, a comparison of conformational distributions of unfolded peptide segments in solution and in coil libraries reveal interesting information on how the interplay between intrinsic propensities of amino acid residues and non-local interactions in polypeptide chains determine the conformations of loop segments in proteins.

Protein lysine-Nζ alkylation andO-phosphorylation mediated by DTT-generated reactive oxygen species

Reactive oxygen species (ROS) play crucial roles in physiology and pathology. In this report, we use NMR spectroscopy and mass spectrometry (MS) to demonstrate that proteins (galectin-1, ubiquitin, RNase, cytochrome c, myoglobin, and lysozyme) under reducing conditions with dithiothreitol (DTT) become alkylated at lysine-N(ζ) groups and O-phosphorylated at serine and threonine residues. These adduction reactions only occur in the presence of monophosphate, potassium, trace metals Fe/Cu, and oxygen, and are promoted by reactive oxygen species (ROS) generated via DTT oxidation. Superoxide mediates the chemistry, because superoxide dismutase inhibits the reaction, and hydroxyl and phosphoryl radicals are also likely involved. While lysine alkylation accounts for most of the adduction, low levels of phosphorylation are also observed at some serine and threonine residues, as determined by western blotting and MS fingerprinting. The adducted alkyl group is found to be a fragment of DTT that forms a Schiff base at lysine N(ζ) groups. Although its exact chemical structure remains unknown, the DTT fragment includes a SH group and a --CHOH--CH₂-- group. Chemical adduction appears to be promoted in the context of a well-folded protein, because some adducted sites in the proteins studied are considerably more reactive than others and the reaction occurs to a lesser extent with shorter, unfolded peptides and not at all with small organic molecules. A structural signature involving clusters of positively charged and other polar groups appears to facilitate the reaction. Overall, our findings demonstrate a novel reaction for DTT-mediated ROS chemistry with proteins.

Aromatic Amino Acids Confer Folding Propensities to a Nine-Residue Peptide

We investigated how individual amino acids affect the structural propensities of short peptides. We based our work on NMR measurements of peptides of sequence EGAAXAASS, where 15 different amino acids were tested at position X. Here we focus on the two peptides with X = Trp and Gly, especially on their residual dipolar couplings (RDC). The pattern of the peptide with X = Gly was rather flat, suggesting an extended or unfolded peptide, while the pattern of the peptide with X = Trp was particularly contrasted, characterized by a changing sign value in the middle of the chain, suggesting for us the formation of a helical turn. The molecular dynamics (MD) simulations confirmed theses hypotheses. In the simulations, the peptide with X = Gly was extended most of the time and calculated RDCs were in good agreement with the experimental one. In contrast, the peptide with X = Trp showed many different conformations, mostly folded but with a non negligible number of extended conformations. After clustering the conformations according to the dihedral angles of the main chain, we found that the clusters with theoretical RDCs that better fit the experimental data were those forming a helical turn. We also show that the driving force leading to such folded conformation could arise from the lack of hydration of the peptide chain on either side of the bulky aromatic residue.

Fast Dynamics of HP35 for Folded and Urea-Unfolded Conditions

The changes in fast dynamics of HP35 with a double CN vibrational dynamics label (HP35-P(2)) as a function of the extent of denaturation by urea were investigated with two-dimensional infrared (2D IR) vibrational echo spectroscopy. Cyanophenylalanine (PheCN) replaces the native phenylalanine at two residues in the hydrophobic core of HP35, providing vibrational probes. NMR data show that HP35-P(2) maintains the native folded structure similar to wild type and that both PheCN residues share essentially the same environment within the peptide. A series of time-dependent 2D IR vibrational echo spectra were obtained for the folded peptide and the increasingly unfolded peptide. Analysis of the time dependence of the 2D spectra yields the system's spectral diffusion, which is caused by the sampling of accessible structures of the peptide under thermal equilibrium conditions. The structural dynamics become faster as the degree of unfolding is increased.

Spectroscopic and Computational Study of Melittin, Cecropin A, and the Hybrid Peptide CM15

Antimicrobial peptides (AMPs), such as cecropin A from silk moth, are key components of the innate immune system. They are effective defensive weapons against invading pathogens, yet they do not target host eukaryotic cells. In contrast, peptide toxins, such as honeybee melittin, are nondiscriminating and target both eukaryotic and prokaryotic cells. An AMP-toxin hybrid peptide that is composed of cecropin A and melittin (CM15) improves upon the antimicrobial activity of cecropin A without displaying the nonspecific, hemolytic properties of melittin. Here we report fluorescence and UV resonance Raman spectra of melittin, cecropin A, and CM15 with the goal of elucidating peptide-membrane interactions that help guide specificity. We have probed the potency for membrane disruption, local environment and structure of the single tryptophan residue, backbone conformation near the peptide hinge, and amide backbone structure of the peptides in lipid environments that mimic eukaryotic and prokaryotic membranes. These experimental results suggest that melittin inserts deeply into the bilayer, whereas cecropin A remains localized to the lipid headgroup region. A surprising finding is that CM15 is a potent membrane-disruptor despite its largely unfolded conformation. A molecular dynamics analysis complements these data and demonstrates the ability of CM15 to associate favorably with membranes as an unfolded peptide. This combined experimental–computational study suggests that new models for peptide–membrane interactions should be considered.

A PagP fusion protein system for the expression of intrinsically disordered proteins in Escherichia coli

PagP, a beta-barrel membrane protein found in Gram-negative bacteria, expresses robustly in inclusion bodies when its signal sequence is removed. We have developed a new fusion protein expression system based on PagP and demonstrated its utility in the expression of the unstructured N-terminal region of human cardiac troponin I (residues 1–71). A yield of 100mg fusion protein per liter M9 minimal media was obtained. The troponin I fragment was removed from PagP using cyanogen bromide cleavage at methionine residues followed by nickel affinity chromatography. We further demonstrate that optimal cleavage requires complete reduction of methionine residues prior to cyanogen bromide treatment, and this is effectively accomplished using potassium iodide under acidic conditions. The PagP-based fusion protein system is more effective at targeting proteins into inclusion bodies than a commercially available system that uses ketosteroid isomerase; it thus represents an important advance for producing large quantities of unfolded peptides or proteins in Escherichia coli.

Moonlighting Peptides with Emerging Function

Hunter-killer peptides combine two activities in a single polypeptide that work in an independent fashion like many other multi-functional, multi-domain proteins. We hypothesize that emergent functions may result from the combination of two or more activities in a single protein domain and that could be a mechanism selected in nature to form moonlighting proteins. We designed moonlighting peptides using the two mechanisms proposed to be involved in the evolution of such molecules (i.e., to mutate non-functional residues and the use of natively unfolded peptides). We observed that our moonlighting peptides exhibited two activities that together rendered a new function that induces cell death in yeast. Thus, we propose that moonlighting in proteins promotes emergent properties providing a further level of complexity in living organisms so far unappreciated.

A Lon-Like Protease with No ATP-Powered Unfolding Activity

Lon proteases are a family of ATP-dependent proteases involved in protein quality control, with a unique proteolytic domain and an AAA+ (ATPases associated with various cellular activities) module accommodated within a single polypeptide chain. They were classified into two types as either the ubiquitous soluble LonA or membrane-inserted archaeal LonB. In addition to the energy-dependent forms, a number of medically and ecologically important groups of bacteria encode a third type of Lon-like proteins in which the conserved proteolytic domain is fused to a large N-terminal fragment lacking canonical AAA+ motifs. Here we showed that these Lon-like proteases formed a clade distinct from LonA and LonB. Characterization of one such Lon-like protease from Meiothermus taiwanensis indicated that it formed a hexameric assembly with a hollow chamber similar to LonA/B. The enzyme was devoid of ATPase activity but retained an ability to bind symmetrically six nucleotides per hexamer; accordingly, structure-based alignment suggested possible existence of a non-functional AAA-like domain. The enzyme degraded unstructured or unfolded protein and peptide substrates, but not well-folded proteins, in ATP-independent manner. These results highlight a new type of Lon proteases that may be involved in breakdown of excessive damage or unfolded proteins during stress conditions without consumption of energy.

Thermodynamics of peptide dimer formation

The Replica Exchange Statistical Temperature Molecular Dynamics algorithm is used to study the equilibrium properties of a peptide monomer and dimer and the thermodynamics of peptide dimer formation. The simulation data are analyzed by the Statistical Temperature Weighted Histogram Analysis Method. Each 10-residue peptide is represented by a coarse-grained model with hydrophobic side chains and has an α-helix as its minimum energy configuration. It is shown that the configurational behavior of the dimer can be divided into four regions as the temperature increases: two folded peptides; one folded and one unfolded peptide; two unfolded peptides; and two spatially separated peptides. Two important phenomena are discussed: in the dimer, one peptide unfolds at a lower temperature than the isolated monomer and the other peptide unfolds at a higher temperature than the isolated monomer. In addition, in the temperature region where one peptide is folded and the other unfolded, the unfolded peptide adopts an extended structure that minimizes the overall surface area of the aggregate. It is suggested that combination of destabilization due to aggregation and the resulting extended configuration of the destabilized peptide could have implications for nucleating β-sheet structures and the ultimate formation of fibrils.

Test of a method for sampling the internal degrees of freedom of a flexible solute molecule based on adiabatic decoupling and temperature or force scaling

Simulation of the folding equilibrium of a polypeptide in solution is a computational challenge. Standard molecular dynamics (MD) simulations of such systems cover hundreds of nanoseconds, which is barely sufficient to obtain converged ensemble averages for properties that depend both on folded and unfolded peptide conformations. If one is not interested in dynamical properties of the solute, techniques to enhance the conformational sampling can be used to obtain the equilibrium properties more efficiently. Here the effect on particular equilibrium properties at 298 K of adiabatically decoupling the motion a β-hepta-peptide from the motion of the solvent and subsequently up-scaling its temperature or down-scaling the forces acting on it is investigated. The ensemble averages and rate of convergence are compared to those for standard MD simulations at two different temperatures and a simulation in which the temperature of the solute is increased to 340 K while keeping the solvent at 298 K. Adiabatic decoupling with a solute mass scaling factor s m = 100 and a temperature scaling factor of s T = 1.1 seems to slightly increase the convergence of several properties such as enthalpy of folding, NMR NOE atom–atom distances and 3J-couplings compared to a standard MD simulation at 298 K. Convergence is still slower than that observed at 340 K. The system with a temperature of 340 K for the solute and 298 K for the solvent without scaling of the mass converges fastest. Using a force scaling factor s V = 0.909 perturbs the system too much and leads to a destabilization of the folded structure. The sampling efficiency and possible distortive effects on the configurational distribution of the solute degrees of freedom due to adiabatic decoupling and temperature or force scaling are also analysed for a simpler model, a dichloroethane molecule in water. It appears that an up-scaling of the mass of the solute reduces the sampling more than the subsequent up-scaling of the temperature or down-scaling of the force enhances it. This means that adiabatic decoupling the solute degrees of freedom from the solvent ones followed by an up-scaling of temperature of down-scaling of the forces does not lead to significantly enhanced sampling of the folding equilibrium.

Curcumin Prevents Aggregation in α-Synuclein by Increasing Reconfiguration Rate

α-Synuclein is a protein that is intrinsically disordered in vitro and prone to aggregation, particularly at high temperatures. In this work, we examined the ability of curcumin, a compound found in turmeric, to prevent aggregation of the protein. We found strong binding of curcumin to α-synuclein in the hydrophobic non-amyloid-β component region and complete inhibition of oligomers or fibrils. We also found that the reconfiguration rate within the unfolded protein was significantly increased at high temperatures. We conclude that α-synuclein is prone to aggregation because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs. Curcumin rescues the protein from aggregation by increasing the reconfiguration rate into a faster regime.

Transferability of Various Molecular Property Tensors in Vibrational Spectroscopy.

Transfers of polarizability, dipole, and energy derivatives from smaller fragments enable extension of ab initio vibrational spectral simulations to larger molecules. The accuracy of the transfer, however, varies according to the molecule and the tensor type. Recent works (J. Chem. Theory Comput.2011, 7, 1867 and Coll. Czech. Chem. Commun.2011, 76, 567) questioned the accuracy of the tensor transfer for Raman optical activity (ROA) spectra. To estimate relative errors, the current study systematically compares transfer properties for four spectral types (ROA, Raman, vibrational circular dichroism (VCD), and infrared absorption (IR)). As test molecules, polyglycine and polyproline peptides in polyproline II and α-helical conformations were used. The results indicate that the discrepancies could be caused by variation of the transfer parameters but not by fundamental differences in the ROA tensor properties. In particular, when done consistently, the transferred electric and magnetic dipole derivatives, polarizability tensors, and harmonic force field provided a reasonable convergence of all spectra for transfers with increasing sizes of the fragments. The polarized spectroscopies (VCD and ROA), however, were found to be significantly more sensitive than the unpolarized (IR, Raman) ones. Optimization of the geometry and the character of the amino acid side chain was relatively unimportant for the transfer. On the other hand, intramolecular hydrogen bonds in the helix required larger fragments for the same accuracy than in an unfolded peptide. Nevertheless, with reasonable fragmentation, all the spectra (IR, VCD, Raman, and ROA) of the target structures could be reconstructed to an accuracy sufficient for a full interpretation of the experiment, with substantial savings of computer time as an added benefit.

Is the Amino Acid Dipeptide a Suitable Model for Investigating Structural Preferences in the Unfolded State?

In view of many observations of local order within unfolded peptides and proteins, intrinsic conformational propensities of individual amino acid residues have been warranted for an understanding of how the conformational distributions in unfolded proteins affect protein folding. Various and sundry experimental and computational techniques have produced conflicting conformational sampling distributions even when similar unfolded model systems were employed. One of the most utilized model systems have been the amino acid dipeptides because the classical definition of the unfolded state was supported by the Ramachandran plot of the alanine dipeptide, which exhibited a nearly homogeneous sampling of sterically allowed conformations. Many studies on amino acid dipeptides have indicated that conformational preferences vary between different amino acids. In order to quantify these differences, we measured the amide I’ band profiles of dipeptides in water using infrared absorption, vibrational circular dichroism, and Raman spectroscopy. A conformational distribution model was utilized in order to reproduce all experimental data, which was further constrained by 3J(NHNα) and 1J(C’Cα) coupling constants. For alanine, our results suggest that it samples much less PPII-like conformations in a dipeptide than in GAG. Our experimental results were confirmed by results from Molecular Dynamics simulations. A first analysis of data obtained for other dipeptides also suggest reduced PPII fractions. We tentatively assign this to different hydration shells of blocked and unblocked peptides.

Replica Exchange Statistical Temperature Molecular Dynamics Simulations of Peptide Dimerization

We present a new computer simulation algorithm called Replica Exchange Statistical Temperature Molecular Dynamics that combines the multicanonical sampling technique of Statistical Temperature Molecular Dynamics with temperature replica exchange. This algorithm is related to Wang-Landau sampling but uses a dynamical update of the density of states to achieve flat energy sampling within a replica-dependent temperature range. This algorithm is used to investigate the thermodynamics of dimerization of two polypeptide chains. Three two-peptide systems are investigated: two hydrophobic peptides, two hydrophilic peptides, and one of each. Each monomer is modeled using a coarse-grained peptide model that has an α-helix as the lowest energy configuration. For each dimer system, interesting folding behavior is observed. It is found that at low temperatures, both peptides are helical and the lowest-energy configuration maximizes inter-peptide contact; at high temperatures, both peptides are random coils; and at intermediate temperatures, one peptide is folded and the other unfolded. Formation of the peptide dimer causes one peptide to fold at a higher temperature than an isolated monomer and the other to fold at a lower temperature than an isolated monomer. Dimerization causes one peptide to become more stable and the other peptide to become less stable. It is also shown that at intermediate temperatures, neither peptide adopts a random coil configuration: the helical peptide induces a conformational change in the unfolded peptide. The Potential Energy Surface (PES) is also determined for each dimer and the effect of hydrophobic/hydrophilic nature of the peptide on the PES is discussed.

Conformational propensities and residual structures in unfolded peptides and proteins

Ample evidence gathered over the last ten years indicates that unfolded and naturally disordered proteins and peptides can show local order in that short segments can adopt turn or polyproline II-like conformations. These findings show that unfolded states cannot be described by the so-called random coil model which assumes that individual amino acid residues sample the entire sterically accessible parts of the Ramachandran with very similar probabilities. This article reviews the experimental evidence for the notion that amino acid residues have different propensities for polyproline II, β-strand, helical and turn conformations in water. These propensities are changed by interactions with nearest neighbours. We show that for a substantial number of residues the conformational propensities in the unfolded state correlate with values for helix propagation and the Chou-Fasman propensities for β-strands. Based on the presented results we hypothesize that the conformational distributions of a representative set of short peptides could be used for predicting structural distributions of disordered peptides and proteins in the future.

Molecular Dynamics Prediction and Refinement of Transmembrane Helix Dimers

Membrane proteins represent around one fourth of all proteins encoded in genomes. Amongst these transmembrane (TM) proteins span the entire lipid bilayer, and -by allowing information to be transmitted across the membrane- play important roles in cell biology and physiology. Several mechanisms for such signal transduction have been revealed, ranging from conformational changes in protein channels and pumps to alterations in helix structures that regulate the activity of intra- and extracellular domains in TM receptors. We have begun to investigate the role of TM helix association in single pass receptors, such as the Eph and plexin receptor. Often the structures of the TM helix associated states are not known and a number of laboratories have been trying to fill this void by use of molecular modeling and dynamics for structure prediction.This work explores a plausible route to predicting structures of transmembrane helix dimers that combines two layers of modeling. The method is applied to known helix dimer structures as a validation study. Starting from a pair of unfolded peptides, thorough sampling is performed using an implicit bilayer potential to generate starting configurations that are then relaxed in an explicit bilayer. Helix crossing angles for EphA1 and ErbB1/2 dimers obtained from the explicit bilayer ensembles are in very good agreement with experiment. (Crossing angles from the implicit simulations are incorrect.) The predicted helix packing residues differ from experiment. It is possible the 100 ns simulation times are insufficient for a sampling of helix rotation and thereby a satisfactory determination of the residues involved in helix-helix packing.

Effects of solvents on the intrinsic propensity of peptide backbone conformations

We investigated the effects of solvents on the intrinsic propensity of peptide backbone conformations based on molecular dynamics simulations. The results show that compared with pure water, aqueous urea decreases the helix propensity. In comparison, methanol decreases the polyproline II (PPII) propensity. Such a solvent dependence of the intrinsic propensity of the backbone conformation is correlated with the solvent dependence of the hydration of the backbone groups and the formation probability of the local intrapeptide hydrogen bonds. Aqueous urea which has low ability to stabilize the local intrapeptide hydrogen bonds disfavors the helical conformation. Whereas, methanol which has low ability to hydrate the backbone groups disfavors the polyproline II conformation. In addition, the solvent effects can be further modulated by the side chains of the peptides. The solvent effects of the intrinsic propensity of peptide backbone conformations observed in this work suggest that changing the intrinsic propensity of the protein backbone conformations can partly contribute to the solvent-induced protein structure and dynamics variations. These results will be useful in understanding the solvent dependence of the conformational distributions of the unfolded proteins or peptides (or intrinsically disordered proteins) in which the global tertiary interactions are less important than that in the well-folded proteins.