Helix-Forming Tendencies of Amino Acids in Short (Hydroxybutyl)-L-glutamine Peptides: An Evaluation of the Contradictory Results from Host-Guest Studies and Short Alanine-Based Peptides

Padmanabhan, S.; York, Eunice J.; Gera, Lajos; Stewart, John M.; Baldwin, Robert L.

doi:10.1021/bi00194a027

Cited by 33 publications

(32 citation statements)

References 31 publications

(31 reference statements)

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“…Experimental measurements of the helix-coil transitions of synthetic polypeptides in solution were successfully modeled to account for the cooperativity of the helix-coil transition (Schellman, 1958;Zimm & Bragg, 1959;Poland & Scheraga, 1970;Scholtz & Baldwin, 1992). Studies of model peptides have established a quantitative understanding of the energetic contributions of the different amino acids to helix-coil transitions in water (Sueki et al, 1984;Lyu et al, 1990;O'Neil & DeGrado, 1990;Chakrabartty et al, 1991;Scholtz et al, 1991;Dyson et al, 1992aDyson et al, , 1992bScholtz & Baldwin, 1992;Vila et al, 1992;Padmanabhan et al, 1994), their capping interactions (Harper & Rose, 1993;Lyu et al, 1993). and the stabilities of turns in model peptides in solution (Wright et al, 1988).…”

Section: Local Interactions and Hydrogen Bondingmentioning

confidence: 99%

Principles of protein folding — A perspective from simple exact models

et al. 1995

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General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics-fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse.Keywords: chain collapse; hydrophobic interactions; lattice models; protein conformations; protein folding; protein stabilityWe review the principles of protein structure, stability, and folding kinetics from the perspective of simple exact models. We focus on the "folding code''-how the tertiary structure and folding pathway of a protein are encoded in its amino acid sequence. Although native proteins are specific, compact, and often remarkably symmetrical structures, ordinary synthetic polymers in solution, glasses, or melts adopt large ensembles of more expanded conformations, with little intrachain organization. With simple exact models, we ask what are the fundamental causes of the differences between proteins and other polymers-What makes proteins special?One view of protein folding assumes that the "local" interactions among the near neighbors in the amino acid sequence, the interactions that form helices and turns, are the main determinants of protein structure. This assumption implies that isolated helices form early in the protein folding pathway and then assemble into the native tertiary structure (see Fig. 1). It is the premise behind the paradigm, primary + secondary -+ tertiary structure, that seeks computer algorithms to predict secondary structures from the sequence, and then to assemble them into the tertiary native structure.Here we review a simple model of an alternative view, its basis in experimental results, and its implications. We show how the nonlocal interactions that drive collapse processes in heteropolymers can give rise to protein structure, stability, and folding kinetics. This perspective is based on evidence that the folding code is not predominantly localized in short windows of the amino acid sequence. It...

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Section: Local Interactions and Hydrogen Bondingmentioning

confidence: 99%

Principles of protein folding — A perspective from simple exact models

et al. 1995

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“…One suggestion is that effects of context might be more pervasive than originally supposed (Groebke et al, 1996). Scheraga's group pioneered development of a propensity scale using a bulky synthetic host side chain, which demonstrably can influence substitutions at sites several positions away (Padmanabhan et al, 1994). Baldwin's and Stellwagen's groups, on the other hand, have argued that the minimal helix forming side chain of alanine is intrinsically a better reference, although even alanine is capable of promoting interactions from neighboring side chains (Groebke et al, 1996).…”

Section: 5mentioning

confidence: 99%

“…ature and concentration on the stability of a-helix (Marqusee et al, 1987;Shoemaker et al, 1987;Lyu et al, 1990;Finkelstein et al, 1991), the role of individual side chains and side-chain-side-chain interactions (Kim et al, 1982;Lyu et al, 1990Lyu et al, , 1992aFinkelstein et al, 1991), position effects of amino acid substitutions in short peptides (Padmanabhan et al, 1990;Chakrabartty et al, 1991;Padmanabhan et al, 1991;Lyu et al, 1992a), as well as N and C terminal capping effects (Lyu et al, 1992b(Lyu et al, , 1993 have all been studied using CD spectroscopy to assess helix content. In addition, the distribution of helical structure has been determined using 'H NMR (Liff et al, 1991;Lyu et al, 1993) while titration studies and DSC analysis have provided an estimate of the heat of formation for a-helix (Ptitsyn, 1972;Scholtz et al, 1991b), approximately 1 kcal/mol residues.…”

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The role of context on α‐helix stabilization: Host‐guest analysis in a mixed background peptide model

et al. 1997

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The helix content of a series of peptides containing single substitutions of the 20 natural amino acids in a new designed host sequence, succinyl-YSEEEEKAKKAXAEEAEKKKK-NH2, has been determined using CD spectroscopy. This host is related to one previously studied, in which triple amino acid substitutions were introduced into a background of Glu-Lys blocks completely lacking alanine. The resulting free energies show that only Ala and Glu-prove to be helix stabilizing, while all other side chains are neutral or destabilizing. This agrees with results from studies of alanine-rich peptide models, but not the previous Glu-Lys block oligomers in which Leu and Met also stabilize helix. The helix propensity scale derived from the previous block oligomers correlated well with the frequencies of occurrence of different side chains in helical sequences of proteins, whereas the values from the present series do not. The role of context in determining scales of helix propensity values is discussed, and the ability of algorithms designed to predict helix structure from sequence is compared.

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“…Intrinsic preferences were first measured in a host-guest system of random copolymers (Sueki et al, 1984;Wojcik et al, 1990), but these results gave poor agreement with data from peptides with defined sequences. The reason was investigated by Padmanabhan et al (1994). Helix preferences have also been measured in shorter isolated helices Merutka & Stellwagen, 1990;, in proteins (Horovitz et al, 1992;Blaber et al, Reprint requests to: Robert L. Baldwin, Department of Biochemistry, Stanford University Medical Center, Stanford, California 94305.…”

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confidence: 99%

N‐ and C‐capping preferences for all 20 amino acids in α‐helical peptides

1995

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We have determined the N-and C-capping preferences of all 20 amino acids by substituting residue X in the peptides NHz-XAKAAAAKAAAAKAAGY-CONHz and in Ac-YGAAKAAAAKAAAAKAX-C0,H. Helix contents were measured by CD spectroscopy to obtain rank orders of capping preferences. The data were further analyzed by our modified Lifson-Roig helix-coil theory, which includes capping parameters (n and c), to find free energies of capping (-RT In n and -RT In c), relative to Ala. Results were obtained for charged and uncharged termini and for different charged states of titratable side chains. N-cap preferences varied from Asn (best) to Gln (worst). We find, as expected, that amino acids that can accept hydrogen bonds from otherwise free backbone NH groups, such as Asn, Asp, Ser, Thr, and Cys generally have the highest N-cap preference. Gly and the acetyl group are favored, as are negative charges in side chains and at the N-terminus. Our N-cap preference scale agrees well with preferences in proteins. In contrast, we find little variation when changing the identity of the C-cap residue. We find no preference for Gly at the C-cap in contrast to the situation in proteins. Both N-cap and C-cap results for Tyr and Trp are inaccurate because their aromatic groups affect the CD spectrum. The data presented here are of value in rationalizing mutations at capping sites in proteins and in predicting the helix contents of peptides.Keywords: a-helix; C-cap; circular dichroism; helix propensities; N-cap; modified Lifson-Roig theory; protein folding; protein stabilityThe a-helix is the most commonly occurring secondary structural element in proteins. It has been known for some time that different amino acids show varied preferences for different secondary structures (Chou & Fasman, 1974). Since then, there has been a considerable amount of work on experimentally measuring the preference of the amino acids for the a-helix. Most studies concentrated on the solvent-exposed surface of a central position of an a-helix (reviewed by Baldwin, 1992, and. Intrinsic preferences were first measured in a host-guest system of random copolymers (Sueki et al., 1984;Wojcik et al., 1990), but these results gave poor agreement with data from peptides with defined sequences. Recently it has been realized that helix preferences differ greatly between interior positions and the helix termini. The N-terminus of a helix has four amide hydrogens that lack the i-(i + 4) backbone hydrogen bonds that characterize the a-helix; similarly, the C-terminus has four free carbonyl groups. Presta and Rose (1988) suggested that hydrogen bonds from polar side chains to these otherwise unsatisfied hydrogen bonding partners are of critical importance in establishing the locations of helix termini. The residue immediately preceding the N-terminal side of the helix has been dubbed the N-cap, whereas the residue immediately following the C-terminal side of the helix is the C-cap.The capping residues have nonhelical(c#+ 4) dihedral angles. The observed distributions of ami...

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Helix-Forming Tendencies of Amino Acids in Short (Hydroxybutyl)-L-glutamine Peptides: An Evaluation of the Contradictory Results from Host-Guest Studies and Short Alanine-Based Peptides

Cited by 33 publications

References 31 publications

Principles of protein folding — A perspective from simple exact models

Principles of protein folding — A perspective from simple exact models

The role of context on α‐helix stabilization: Host‐guest analysis in a mixed background peptide model

N‐ and C‐capping preferences for all 20 amino acids in α‐helical peptides

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