Validation of an All-Atom Protein Force Field:  From Dipeptides to Larger Peptides

Gnanakaran, S.; Garcı́a, Angel E.

doi:10.1021/jp0359079

Cited by 113 publications

(188 citation statements)

References 21 publications

(55 reference statements)

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“…The result of their MD simulations led Makowska et al (30) to the conclusion that PPII is only one of many possible conformations sampled by alanine residues, and that the notion of a PPII propensity for alanine has to be rejected. This finding is at variance with results obtained from experimental investigations on short peptides (6,36,37), which are clearly indicative of a PPII propensity for alanine, in accordance with recent MD simulations of Gnanakaran and Garcia (28,55). On the other hand, it was clear that the radius of gyration value obtained from SAXS experiments was inconsistent with a predominant PPII population for all alanine residues of the XAO peptide.…”

Section: Resultssupporting

confidence: 84%

The alanine-rich XAO peptide adopts a heterogeneous population, including turn-like and polyproline II conformations

Schweitzer‐Stenner

Measey

2007

Proc. Natl. Acad. Sci. U.S.A.

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The solution structure of the hepta-alanine polypeptide Ac-X 2A7O2-NH2 (XAO) has been a matter of controversy in the current literature. On one side of the argument is a claim that the peptide adopts a mostly polyproline II ( We have used an excitonic coupling model to simulate the amide I band of the FTIR, vibrational circular dichroism, and isotropic and anisotropic Raman spectra of XAO, where, for each residue, the backbone dihedral angle was constrained by using the reported 3 JC␣HNH values and a modified Karplus relation. The best reproduction of the experimental data could only be achieved by assuming an ensemble of conformations, which contains various ␤-turn conformations (Ϸ26%), in addition to ␤-strand (Ϸ23%) and PPII (Ϸ50%) conformations. PPII is the dominant conformation in segments not involved in turn formations. Most of the residues were found to sample the bridge region connecting the PPII and right-handed helix troughs in the Ramachandran plot, which is part of the very heterogeneous ensemble of conformations generally termed type IV ␤-turn.alanine propensity ͉ amide I ͉ unfolded peptides ͉ vibrational spectroscopy T he unfolded state of peptides and proteins has been the subject of an increasing number of experimental and theoretical studies (1-9), owing to the discovery of naturally disordered, although biologically functioning, proteins and peptides (9), and the general relevance for a thorough understanding of the protein folding process. In this context, the possible existence of local residue structure would certainly affect the initial phase of the folding process (10). The existence of such locally ordered segments has first been proposed by Tiffany and Krimm (11) based on electronic circular dichroism (ECD) measurements on poly-L-proline, poly-L-lysine, and poly-L-glutamic acid. They concluded that charged polypeptides assume, at least locally, a rather ordered polyproline II (PPII) conformation, which is the structure adopted by trans-poly-L-proline. This notion was later confirmed by vibrational circular dichroism (VCD) studies on a variety of unfolded polypeptides and proteins (12,13).PPII is a rather regular structural motif in that it exhibits a perfect, left-handed threefold rotational symmetry (3 1 -helix) for its canonical conformation, with ( , ) ϭ (Ϫ78°, 146°) (14). Woody and coworkers (15-17) have published a series of papers proving that PPII gives rise to a far UV-ECD spectrum, which many in the scientific community still interpret as indicative of random coil (15). Recently, they reported a very convincing quantitative agreement between the PPII content of ␤II proteins, derived from crystallographic data, and ECD spectra (16). The PPII signal was also observed in the spectrum of the unfolded state of many proteins subjected to denaturing detergents (17). Thermal denaturation, however, often yields a conformation that is reflected by a weak, nearly symmetric, couplet with a positive maximum between 180 and 210 nm and a negative minimum between 210 and 230 nm (11,16,18). ECD ...

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Section: Resultssupporting

confidence: 84%

The alanine-rich XAO peptide adopts a heterogeneous population, including turn-like and polyproline II conformations

Schweitzer‐Stenner

Measey

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…According to Flory (5) and Tanford (6), unfolded proteins can be represented as statistical random coils, in which a given residue has no strong preference for any specific conformation. Confirming earlier conclusions by Tiffany and Krimm (7)(8)(9), recent evidence from a variety of spectroscopic probes (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), theoretical studies (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and coil library surveys (35)(36)(37)(38)(39)(40)(41)(42)(43)) consistently point to a major role for the polyproline II (PPII, ⌽ ϭ Ϫ75°, ⌿ ϭ ϩ145°) conformation in oligo-Ala (for review, see ref. 3 and related articles in the same volume), oligo-Lys, and oligo-Glu peptides (44).…”

supporting

confidence: 73%

Polyproline II propensities from GGXGG peptides reveal an anticorrelation with β-sheet scales

Shi

Kang

Liu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

151

304

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There is growing appreciation of the functional relevance of unfolded proteins in biology. However, unfolded states of proteins have proven inaccessible to the usual techniques for high-resolution structural and energetic characterization. Unfolded states are still generally conceived of as statistical coils, based on the pioneering work of Flory [(1969 T he process by which a protein acquires its native structure is among the most complex reactions known, and challenges remain in defining the nature of the transition state(s), the structure and role of intermediates, and the properties of the starting ensemble of states (1-4). According to Flory (5) and Tanford (6), unfolded proteins can be represented as statistical random coils, in which a given residue has no strong preference for any specific conformation. Confirming earlier conclusions by Tiffany and Krimm (7-9), recent evidence from a variety of spectroscopic probes (10-22), theoretical studies (23-34), and coil library surveys (35-43) consistently point to a major role for the polyproline II (PPII, ⌽ ϭ Ϫ75°, ⌿ ϭ ϩ145°) conformation in oligo-Ala (for review, see ref. 3 and related articles in the same volume), oligo-Lys, and oligo-Glu peptides (44). We have reported that in a seven-Ala peptide model PPII converts to a ␤-like structure with increasing temperature (13). These findings raise several important questions regarding the structure of unfolded proteins: Although alanine is arguably a reasonable model for the unperturbed peptide backbone, is PPII also present in unfolded peptide chains composed of nonalanine nonproline residues? Is there an intrinsic PPII propensity for each individual side chain? If PPII is in equilibrium with ␤-structure, is there a correlation between scales of PPII propensity and analogous ␤-sheet scales? To what extent is PPII sequence and context dependent?Here, we address these questions by analyzing a series of end-blocked host pentapeptides AcGGXGGNH 2 , where X denotes 19 natural amino acids except glycine. Members of the series are found to differ in their extent of PPII conformation as determined by NMR and CD spectroscopy. Our results lead to the following conclusions: PPII is present as a dominant conformation in the majority of AcGGXGGNH 2 peptides. Different side chains show distinct propensities to adopt PPII in these unfolded molecules. Importantly, we find an inverse correlation between the determined PPII scale and the ␤-sheet-forming propensities derived from a zinc-finger model system (45) when 18 aa (except Gly and Pro) are divided into two groups: one, the nonpolar ␤-branched and bulky aromatic residues (VIWFY) and the other all of the remaining side chains. Finally, we find a correlation between our PPII scale in AcGGXGGNH 2 and a PPII scale derived from alternative model peptides such as AcPPPXPPPGYNH 2 (46). Still there are indications that the PPII scale is likely to be sequence and context dependent (47). Materials and MethodsPeptides Synthesis and Purification. Peptides were assembled on Rink Amide res...

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“…Once the Asx-turn conformation collapses, it does not re-form, which may be an artifact of the time scale used in these simulations or may point to weaknesses in the peptide force field. 13,14 It is clear that the conformational preference observed for the central backbone region of 1-β is different from that of 1, 1*, and 1-α (Figure 3). The rapid conformational transitions observed in the simulations of 1, 1*, and 1-α generally contrast with the behavior of 1-β, which displays relatively stable conformations for the peptide-backbone φ torsion angles (Figure 4).…”

Section: Molecular Dynamicsmentioning

confidence: 93%

Effects of Glycosylation on Peptide Conformation: A Synergistic Experimental and Computational Study

et al. 2004

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Asparagine-linked glycosylation, the co-translational covalent attachment of carbohydrates to asparagine side chains, has a major effect on the folding, stability, and function of many proteins. The carbohydrate composition in mature glycoproteins is heterogeneous due to modification of the initial oligosaccharide by glycosidases and glycosyltransferases during the glycoprotein passage through the endoplasmic reticulum and Golgi apparatus. Despite the diversity of carbohydrate structures, the core β-D-(GlcNAc) 2 remains conserved in all N-linked glycoproteins. Previously, results from our laboratory showed that the molecular composition of the core disaccharide has a critical and unique conformational effect on the peptide backbone. Herein, we employ a synergistic experimental and computational approach to study the effect of the stereochemistry of the carbohydrate-peptide linkage on glycopeptide structure. A glycopeptide derived from a hemagglutinin protein fragment was synthesized, with the carbohydrate attached to the peptide with an α-linked stereochemistry. Computational and biophysical analyses reveal that the conformations of the peptide and α-and β-linked glycopeptides are uniquely influenced by the attached saccharide. The value of computational approaches for probing the influence of attached saccharides on polypeptide conformation is highlighted.

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Validation of an All-Atom Protein Force Field: From Dipeptides to Larger Peptides

Cited by 113 publications

References 21 publications

The alanine-rich XAO peptide adopts a heterogeneous population, including turn-like and polyproline II conformations

The alanine-rich XAO peptide adopts a heterogeneous population, including turn-like and polyproline II conformations

Polyproline II propensities from GGXGG peptides reveal an anticorrelation with β-sheet scales

Effects of Glycosylation on Peptide Conformation: A Synergistic Experimental and Computational Study

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