Backbone Conformational Preferences Research Articles

Effects of Phosphorylation on Protein Backbone Dynamics and Conformational Preferences.

Phosphorylations are the most common and extensively studied post-translational modification (PTM) of proteins in eukaryotes. They constitute a major regulatory mechanism, modulating protein function, protein-protein interactions, as well as subcellular localization. Phosphorylation sites are preferably located in intrinsically disordered regions and have been shown to trigger structural rearrangements and order-to-disorder transitions. They can therefore have a significant effect on protein backbone dynamics or conformation, but only sparse experimental data are available. To obtain a more general description of how and when phosphorylations have a significant effect on protein behavior, molecular dynamics (MD) currently provides the only suitable framework to study these effects at a large scale in atomistic detail. This study develops a systematic MD simulation framework to explore the influence of phosphorylations on the local backbone dynamics and conformational propensities of proteins. Through a series of glycine-backbone peptides, we studied the effects of amino acid residues including the three most common phosphorylations (Ser, Thr, and Tyr), on local backbone dynamics and conformational propensities. We further extended our study to investigate the interactions of all such residues between position i to positions i + 1, i + 2, i + 3, and i + 4 in such peptides. The final data set comprises structural ensembles for 3393 sequences with more than 1 μs of sampling for each ensemble. To validate the relevance of the results, the structural and conformational properties extracted from the MD simulations are compared to NMR data from the Biological Magnetic Resonance Data Bank. The systematic nature of this study enables the projection of the gained knowledge onto any phosphorylation site in the proteome and provides a general framework for the study of further PTMs. The full data set is publicly available, as a training and reference set.

Classification of RNA backbone conformations into rotamers using 13C' chemical shifts: exploring how far we can go.

The conformational space of the ribose-phosphate backbone is very complex as it is defined in terms of six torsional angles. To help delimit the RNA backbone conformational preferences, 46 rotamers have been defined in terms of these torsional angles. In the present work, we use the ribose experimental and theoretical 13C′ chemical shifts data and machine learning methods to classify RNA backbone conformations into rotamers and families of rotamers. We show to what extent the experimental 13C′ chemical shifts can be used to identify rotamers and discuss some problem with the theoretical computations of 13C′ chemical shifts.

A hybrid, bottom-up, structurally accurate, Go¯-like coarse-grained protein model.

Coarse-grained (CG) protein models in the structural biology literature have improved over the years from being simple tools to understand general folding and aggregation driving forces to capturing detailed structures achieved by actual folding sequences. Here, we ask whether such models can be developed systematically from recent advances in bottom-up coarse-graining methods without relying on bioinformatic data (e.g., protein data bank statistics). We use relative entropy coarse-graining to develop a hybrid CG but Go¯-like CG peptide model, hypothesizing that the landscape of proteinlike folds is encoded by the backbone interactions, while the sidechain interactions define which of these structures globally minimizes the free energy in a unique native fold. To construct a model capable of capturing varied secondary structures, we use a new extended ensemble relative entropy method to coarse-grain based on multiple reference atomistic simulations of short polypeptides with varied α and β character. Subsequently, we assess the CG model as a putative protein backbone forcefield by combining it with sidechain interactions based on native contacts but not incorporating native distances explicitly, unlike standard Go¯ models. We test the model's ability to fold a range of proteins and find that it achieves high accuracy (∼2 Å root mean square deviation resolution for both short sequences and large globular proteins), suggesting the strong role that backbone conformational preferences play in defining the fold landscape. This model can be systematically extended to non-natural amino acids and nonprotein polymers and sets the stage for extensions to non-Go¯ models with sequence-specific sidechain interactions.

Stereochemistry of polypeptoid chain configurations.

Like polypeptides, peptoids, or N-substituted glycine oligomers, have intrinsic conformational preferences due to their amide backbones and close spacing of side chain substituents. However, the conformations that peptoids adopt are distinct from polypeptides due to several structural differences: the peptoid backbone is composed of tertiary amide bonds that have trans and cis conformers similar in energy, they lack a backbone hydrogen bond donor, and have an N-substituent. To better understand how these differences manifest in actual peptoid structures, we analyzed 46 high quality, experimentally determined peptoid structures reported in the literature to extract their backbone conformational preferences. One hundred thirty-two monomer dihedral angle pairs were compared to the calculated energy landscape for the peptoid Ramachandran plot, and were found to fall within the expected minima. Interestingly, only two regions of the backbone dihedral angles ϕ and ψ were found to be populated that are mirror images of each other. Furthermore, these two conformers are present in both cis and trans forms. Thus, there are four primary conformers that are sufficient to describe almost all known backbone conformations for peptoid oligomers, despite conformational constraints imposed by a variety of side chains, macrocyclization, or crystal packing forces. Because these conformers are predominant in peptoid structure, and are distinct from those found in protein secondary structures, we propose a simple naming system to aid in the description and classification of peptoid structure.

Inherent Conformational Preferences of Ac‐Gln‐Gln‐NHBn: Sidechain Hydrogen Bonding Supports a β‐Turn in the Gas Phase

AbstractGas‐phase single‐conformation spectroscopy is used to study Ac‐Gln‐Gln‐NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide‐rich peptide offers many possibilities for backbone–backbone, sidechain–backbone, and sidechain–sidechain interactions. The major conformer observed experimentally features a type‐I β‐turn with a canonical 10‐membered ring C=O—H−N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven‐membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen‐bonding potential is satisfied in a manner that is consistent with and stabilizes the β‐turn secondary structure. This turn‐forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.

Inherent Conformational Preferences of Ac-Gln-Gln-NHBn: Sidechain Hydrogen Bonding Supports a β-Turn in the Gas Phase.

Gas-phase single-conformation spectroscopy is used to study Ac-Gln-Gln-NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide-rich peptide offers many possibilities for backbone-backbone, sidechain-backbone, and sidechain-sidechain interactions. The major conformer observed experimentally features a type-I β-turn with a canonical 10-membered ring C=O-H-N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven-membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen-bonding potential is satisfied in a manner that is consistent with and stabilizes the β-turn secondary structure. This turn-forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.

Populations of the Minor α-Conformation in AcGXGNH2 and the α-Helical Nucleation Propensities.

Intrinsic backbone conformational preferences of different amino acids are important for understanding the local structure of unfolded protein chains. Recent evidence suggests α-structure is relatively minor among three major backbone conformations for unfolded proteins. The α-helices are the dominant structures in many proteins. For these proteins, how could the α-structures occur from the least in unfolded to the most in folded states? Populations of the minor α-conformation in model peptides provide vital information. Reliable determination of populations of the α-conformers in these peptides that exist in multiple equilibriums of different conformations remains a challenge. Combined analyses on data from AcGXPNH2 and AcGXGNH2 peptides allow us to derive the populations of PII, β and α in AcGXGNH2. Our results show that on average residue X in AcGXGNH2 adopt PII, β, and α 44.7%, 44.5% and 10.8% of time, respectively. The contents of α-conformations for different amino acids define an α-helix nucleation propensity scale. With derived PII, β and α-contents, we can construct a free energy-conformation diagram on each AcGXGNH2 in aqueous solution for the three major backbone conformations. Our results would have broad implications on early-stage events of protein folding.

Intrinsic α‐helical and β‐sheet conformational preferences: A computational case study of alanine

ABSTRACTA fundamental question in protein science is what is the intrinsic propensity for an amino acid to be in an α‐helix, β‐sheet, or other backbone dihedral angle ( ‐ψ) conformation. This question has been hotly debated for many years because including all protein crystal structures from the protein database, increases the probabilities for α‐helical structures, while experiments on small peptides observe that β‐sheet‐like conformations predominate. We perform molecular dynamics (MD) simulations of a hard‐sphere model for Ala dipeptide mimetics that includes steric interactions between nonbonded atoms and bond length and angle constraints with the goal of evaluating the role of steric interactions in determining protein backbone conformational preferences. We find four key results. For the hard‐sphere MD simulations, we show that (1) β‐sheet structures are roughly three and half times more probable than α‐helical structures, (2) transitions between α‐helix and β‐sheet structures only occur when the backbone bond angle τ (NCαC) is greater than 110°, and (3) the probability distribution of τ for Ala conformations in the “bridge” region of ‐ψ space is shifted to larger angles compared to other regions. In contrast, (4) the distributions obtained from Amber and CHARMM MD simulations in the bridge regions are broader and have increased τ compared to those for hard sphere simulations and from high‐resolution protein crystal structures. Our results emphasize the importance of hard‐sphere interactions and local stereochemical constraints that yield strong correlations between ‐ψ conformations and τ.

Energies and 2'-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations.

Sugar-phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2'-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2'-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2'-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2'-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2'-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2'-hydroxyl group orientations can be attributed to clashes between occupied orbitals.

The intrinsic conformational features of amino acids from a protein coil library and their applications in force field development

The local conformational (φ, ψ, χ) preferences of amino acid residues remain an active research area, which are important for the development of protein force fields. In this perspective article, we first summarize spectroscopic studies of alanine-based short peptides in aqueous solution. While most studies indicate a preference for the P(II) conformation in the unfolded state over α and β conformations, significant variations are also observed. A statistical analysis from various coil libraries of high-resolution protein structures is then summarized, which gives a more coherent view of the local conformational features. The φ, ψ, χ distributions of the 20 amino acids have been obtained from a protein coil library, considering both backbone and side-chain conformational preferences. The intrinsic side-chain χ(1) rotamer preference and χ(1)-dependent Ramachandran plot can be generally understood by combining the interaction of the side-chain Cγ/Oγ atom with two neighboring backbone peptide groups. Current all-atom force fields such as AMBER ff99sb-ILDN, ff03 and OPLS-AA/L do not reproduce these distributions well. A method has been developed by combining the φ, ψ plot of alanine with the influence of side-chain χ(1) rotamers to derive the local conformational features of various amino acids. It has been further applied to improve the OPLS-AA force field. The modified force field (OPLS-AA/C) reproduces experimental (3)J coupling constants for various short peptides quite well. It also better reproduces the temperature-dependence of the helix-coil transition for alanine-based peptides. The new force field can fold a series of peptides and proteins with various secondary structures to their experimental structures. MD simulations of several globular proteins using the improved force field give significantly less deviation (RMSD) to experimental structures. The results indicate that the local conformational features from coil libraries are valuable for the development of balanced protein force fields.

Conformational exploration of two peptides and their hybrid polymer conjugates: potentialities as self-aggregating materials.

In this work we elucidate the conformational preferences of two amyloid-forming peptides, Arginine-Vasopressin and Neuromedin-K, and two new biomacromolecular conjugates obtained by linking the two peptides to a polyester (poly(R-lactic acid)) chain. The conformational properties of the new hybrid conjugates have been assessed through molecular dynamics simulations and compared to those of their individual components. Our results suggest that the free unconjugated peptides tend to adopt backbone arrangements which resemble a β-hairpin shape, a conformation which has been reported to facilitate amyloid self-aggregation. The backbone conformational preferences of the unlinked peptides are maintained in the peptide-polymer hybrid. Yet significant differences in the side-chains nonbonding interactions patterns were detected between the two states. This suggests that the conformational profile of the peptides' backbones is preserved when linked to the polymer, maintaining the amyloid precursor-like structure. Additionally, several hydrodynamic parameters were computed for both the polylactic acid and for the conjugates: no significant differences were observed, which suggests that the peptide moiety of the hybrid does not significantly affect the conformational tendencies of the polymer chain. Combined, our results provide a conformational exploration of two amyloid-forming peptides and first steps toward the design of two feasible self-aggregating hybrid materials.

Backbone conformational preferences of an intrinsically disordered protein in solution

We have performed a 4-μs molecular dynamics simulation to investigate the native conformational preferences of the intrinsically disordered kinase-inducible domain (KID) of the transcription factor CREB in solution. There is solid experimental evidence showing that KID does not possess a bound-like structure in solution; however, it has been proposed that coil-to-helix transitions upon binding to its binding partner (CBP) are template-driven. While these studies indicate that IDPs possess a bias towards the bound structure, they do not provide direct evidence on the time-dependent conformational preferences of IDPs in atomic detail. Our simulation captured intrinsic conformational characteristics of KID that are in good agreement with experimental data such as a very small percentage of helical structure in its segment α(B) and structural disorder in solution. We used dihedral principal component analysis dPCA to map the conformations of KID in the microsecond timescale. By using principal components as reaction coordinates, we further constructed dPCA-based free energy landscapes of KID. Analysis of the free energy landscapes showed that KID is best characterized as a conformational ensemble of rapidly interconverting conformations. Interestingly, we found that despite the conformational heterogeneity of the backbone and the absence of substantial secondary structure, KID does not randomly sample the conformational space in solution: analysis of the (Φ, Ψ) dihedral angles showed that several individual residues of KID possess a strong bias toward the helical region of the Ramachandran plot. We suggest that the intrinsic conformational preferences of KID provide a bias toward the folded state without having to populate bound-like conformations before binding. Furthermore, we argue that these conformational preferences do not represent actual structural constraints which drive binding through a single pathway, which allows for specific interactions with multiple binding partners. Based on this evidence, we propose that the backbone conformational preferences of KID provide a thermodynamic advantage for folding and binding without negatively affecting the kinetics of binding. We further discuss the relation of our results to previous studies to rationalize the functional implications of the conformational preferences of IDPs, such as the optimization of structural disorder in protein-protein interactions. This study illustrates the importance in obtaining atomistic information of intrinsically disordered proteins in real time to reveal functional features arising from their complex conformational space.

Phosphorylation alters backbone conformational preferences of serine and threonine peptides

Despite the notion that a control of protein function by phosphorylation works mainly by inducing its conformational changes, the phosphorylation effects on even small peptide conformation have not been fully understood yet. To study its possible effects on serine and threonine peptide conformations, we recently carried out pH- and temperature-dependent circular dichroism (CD) as well as (1)H NMR studies of the phosphorylated serine and threonine peptides and compared them with their unphosphorylated analogs. In the present article, by performing the self-consistent singular value decomposition analysis of the temperature-dependent CD spectra and by analyzing the (3)J(H(N),H(α)) coupling constants extracted from the NMR spectra, the populations of the polyproline II (PPII) and β-strand conformers of the phosphorylated Ser and Thr peptides are determined. As temperature is increased, the β-strand populations of both phosphorylated serine and threonine peptides increase. However, the dependences of PPII/β-strand population ratio on pH are different for these two cases. The phosphorylation of the serine peptide enhances the PPII propensity, whereas that of the threonine peptide has the opposite effect. This suggests that the serine and threonine phosphorylations can alter the backbone conformational propensity via direct but selective intramolecular hydrogen-bonding interactions with the peptide N--H groups. This clearly indicates that the phosphoryl group actively participates in modulating the peptide backbone conformations.

Conformational Preferences and Cis−Trans Isomerization of l-Lactic Acid Residue

The conformational study on N-acetyl- N'-methylamide of l-lactic acid (Ac-Lac-NHMe, the Lac dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore its backbone conformational preferences and cis-trans isomerization for the depsipeptide with an ester bond in the gas phase and in solution. In the gas phase and in chloroform, the conformation tB with a trans depsipeptide bond is most preferred for the Lac dipeptide, whose backbone torsion angles are phi approximately -150 degrees and psi approximately -5 degrees , juxtaposed to those of the 3 10-helical structure. The larger shift in phi is brought to reduce the repulsion between the two carbonyl carbons of the acetyl and NHMe groups. However, the polyproline II-like tF conformation becomes more populated and the relative stability of conformation tB decreases significantly as the solvent polarity increases. This may be ascribed to weakening a C(5) hydrogen bond between the depsipeptidyl oxygen and the carboxyl amide hydrogen that plays a role in stabilizing the conformation tB in the gas phase and in chloroform. The cis populations about the depsipeptide bond are nearly negligible in the gas phase and in solution. The rotational barriers to the cis-trans isomerization of the depsipeptide bond for the Lac dipeptide are calculated to be about 11 kcal/mol, which is about half of those for the Ala dipeptide, although they increase somewhat with the increase of solvent polarity. The cis-trans isomerization of the depsipeptide bond proceeds through either clockwise or anticlockwise rotations with torsion angles of about +90 degrees or -90 degrees , respectively, in the gas phase and in solution, whereas it has been known that the isomerization proceeds through only the clockwise rotation for alanyl and prolyl peptide bonds. The pertinent distances between the depsipeptidyl oxygen and the carboxyl amide hydrogen can describe the role of this hydrogen bond in stabilizing the transition state structures in the gas phase and in solution.

Determination of Conformational Preferences of Dipeptides Using Vibrational Spectroscopy

The NMR coupling constants ((3)J(H(N), H(alpha))) of dipeptides indicate that the backbone conformational preferences vary strikingly among dipeptides. These preferences are similar to those of residues in small peptides, denatured proteins, and the coil regions of native proteins. Detailed characterization of the conformational preferences of dipeptides is therefore of fundamental importance for understanding protein structure and folding. Here, we studied the conformational preferences of 13 dipeptides using infrared and Raman spectroscopy. The main advantage of vibrational spectroscopy over NMR spectroscopy is in its much shorter time scale, which enables the determination of the conformational preferences of short-lived states. Accuracy of structure determination using vibrational spectroscopy depends critically on identification of the vibrational parameters that are sensitive to changes in conformation. We show that the frequencies of the amide I band and the A12 ratio of the amide I components of dipeptides correlate with the (3)J(H(N), H(alpha)). These two infrared vibrational parameters are thus analogous to (3)J(H(N), H(alpha)), indicators for the preference for the dihedral angle phi. We also show that the intensities of the components of the amide III bands in infrared spectra and the intensities of the skeletal vibrations in Raman spectra are indicators of populations of the P(II), beta, and alpha(R) conformations. The results show that alanine dipeptide adopts predominantly a PII conformation. The population of the beta conformation increases in valine dipeptides. The populations of the alpha(R) conformation are generally small. These data are in accord with the electrostatic screening model of conformational preferences.

Statistical coil model of the unfolded state: Resolving the reconciliation problem

An unfolded state ensemble is generated by using a self-avoiding statistical coil model that is based on backbone conformational frequencies in a coil library, a subset of the Protein Data Bank. The model reproduces two apparently contradicting behaviors observed in the chemically denatured state for a variety of proteins, random coil scaling of the radius of gyration and the presence of significant amounts of local backbone structure (NMR residual dipolar couplings). The most stretched members of our unfolded ensemble dominate the residual dipolar coupling signal, whereas the uniformity of the sign of the couplings follows from the preponderance of polyproline II and beta conformers in the coil library. Agreement with the NMR data substantially improves when the backbone conformational preferences include correlations arising from the chemical and conformational identity of neighboring residues. Although the unfolded ensembles match the experimental observables, they do not display evidence of native-like topology. By providing an accurate representation of the unfolded state, our statistical coil model can be used to improve thermodynamic and kinetic modeling of protein folding.

Helix, Sheet, and Polyproline II Frequencies and Strong Nearest Neighbor Effects in a Restricted Coil Library

A central issue in protein folding is the degree to which each residue's backbone conformational preferences stabilize the native state. We have studied the conformational preferences of each amino acid when the amino acid is not constrained to be in a regular secondary structure. In this large but highly restricted coil library, the backbone preferentially adopts dihedral angles consistent with the polyproline II conformation rather than alpha or beta conformations. The preference for the polyproline II conformation is independent of the degree of solvation. In conjunction with a new masking procedure, the frequencies in our coil library accurately recapitulate both helix and sheet frequencies for the amino acids in structured regions, as well as polyproline II propensities. Therefore, structural propensities for alpha-helices and beta-sheets and for polyproline II conformations in unfolded peptides can be rationalized solely by local effects. In addition, these propensities are often strongly affected by both the chemical nature and the conformation of neighboring residues, contrary to the Flory isolated residue hypothesis.

Context‐dependent effects of proline residues on the stability and folding pathway of ubiquitin

Substitution of trans-proline at three positions in ubiquitin (residues 19, 37 and 38) produces significant context-dependent effects on protein stability (both stabilizing and destabilizing) that reflect changes to a combination of parameters including backbone flexibility, hydrophobic interactions, solvent accessibility to polar groups and intrinsic backbone conformational preferences. Kinetic analysis of the wild-type yeast protein reveals a predominant fast-folding phase which conforms to an apparent two-state folding model. Temperature-dependent studies of the refolding rate reveal thermodynamic details of the nature of the transition state for folding consistent with hydrophobic collapse providing the overall driving force. Brønsted analysis of the refolding and unfolding rates of a family of mutants with a variety of side chain substitutions for P37 and P38 reveals that the two prolines, which are located in a surface loop adjacent to the C terminus of the main alpha-helix (residues 24-33), are not significantly structured in the transition state for folding and appear to be consolidated into the native structure only late in the folding process. We draw a similar conclusion regarding position 19 in the loop connecting the N-terminal beta-hairpin to the main alpha-helix. The proline residues of ubiquitin are passive spectators in the folding process, but influence protein stability in a variety of ways.

Theoretical Study of -Peptide Models: Intrinsic Preferences of Helical Structures

β-Peptides form various secondary structures, such as 14-helix, 12-helix, 10/12-helix, 10-helix, 28-ribbon, C6-ribbon, and pleated-sheet. Thus, it is useful to understand the intrinsic backbone conformational preferences of these basic structures. By using a simple repeating-unit method, we have calculated the preferences of C6-ribbon, β-strand, 10/12-helix, 14-helix, 12-helix, 10-helix, and 28-ribbon of a series of poly-β-alanine models, Ac-(β-Ala)n-NH2, with n=1–9. Interactions among single amino acids result in cooperative residue energies. This is not found for the formations of β-strands, 28-ribbons, and C6-ribbons, which possess constant residue energies. In contrast, the 12-helix, 10-helix, and 14-helix are characterized by increasing residue energies as the peptide elongates. Therefore, there is a considerable positive cooperative impetus in the gas phase for their formation. The residue energy of the 10/12-helix increases significantly for n=2 and 3, and then displays a zigzag pattern. Meanwhile, there is a good correlation between calculated residue energies and residue dipole moments, indicating the importance of long-range electrostatic interactions to the cooperative residue energy. Efforts have been made to separate the electrostatic and torsional interactions between residues. Thereby, the 12-, 10-, and 10/12-helices all benefit from electrostatic interactions, while the 14-helix has the most intrinsic preference in terms of torsional interaction. The effect of MeOH on the secondary structures has also been evaluated by SCIPCM solvent model calculations.

The stability of secondary structure in aqueous solution

Conformational thermodynamics determine the ability of peptides to adopt specific secondary structural motifs. In aqueous solution, the preference for a particular motif is strongly influenced by the solvent. We will describe results from our ongoing systematic study of the factors which influence stability of peptide conformations in aqueous solution. Through the use of peptide models containing the simplest amino acids, e.g., ala, gly, pro and val, we have focussed on the intrinsic features of stability as determined solely by peptide backbone conformational preferences, peptide backbone hydrogen bonding and solvent-peptide interactions.In this lecture results for the stability of the hydrogen bond, reverse turns, alpha helices and beta sheets will be presented. Contributions to the stability from solvent induced forces, peptide conformational energetics and entropic factors will be separated to provide a physical picture of the resulting thermodynamics.