Helix stop signals in proteins and peptides: The capping box

Harper, Edwin T.; Rose, George D.

doi:10.1021/bi00081a001

Cited by 340 publications

(325 citation statements)

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“…Notably, this part of HB appears to be stabilized to some degree by the presence of the flexible Nterminus, likely due to contacts [39]. At the top of HC, a so-called 'capping box' interaction [81] may help stabilize the helical structure [82]. For the C-terminal portion of HC, there are also indications that its conformation can be flexible.…”

Section: The Starting Point: Prp Structures From Experimentsmentioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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Section: The Starting Point: Prp Structures From Experimentsmentioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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“…Rapid interconversion and/or bifurcated hydrogen bond formation is likely to be common, especially as N-caps are nearly always on the surface of the protein, where there is more freedom for the side chain to move. (Harper & Rose, 1993).…”

Section: Hydrogen Bonding At the Helix N-terminusmentioning

confidence: 99%

Structures of N‐termini of helices in proteins

et al. 1997

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We have surveyed 393 N-termini of a-helices and 156 N-termini of 310-helices in 85 high resolution, non-homologous protein crystal structures for N-cap side-chain rotamer preferences, hydrogen bonding patterns, and solvent accessibilities. We find very strong rotamer preferences that are unique to N-cap sites. The following rules are generally observed for N-capping in a-helices: Thr and Ser N-cap side chains adopt the gauche-rotamer, hydrogen bond to the N3 NH and have (1, restricted to 164 f 8". Asp and Asn N-cap side chains either adopt the gauche-rotamer and hydrogen bond to the N3 NH with (1, = 172 iz lo", or adopt the trans rotamer and hydrogen bond to both the N2 and N3 NH groups with (1, = 107 Ifr 19". With all other N-caps, the side chain is found in the gauche+ rotamer so that the side chain does not interact unfavorably with the N-terminus by blocking solvation and (1, is unrestricted. An i, i + 3 hydrogen bond from N3 NH to the N-cap backbone C = O in more likely to form at the N-terminus when an unfavorable N-cap is present. In the 310-helix Asn and Asp remain favorable N-caps as they can hydrogen bond to the N2 NH while in the trans rotamer; in contrast, Ser and Thr are disfavored as their preferred hydrogen bonding partner (N3 NH) is inaccessible. This suggests that Ser is the optimum choice of N-cap when a-helix formation is to be encouraged while 310-helix formation discouraged. The strong energetic and structural preferences found for N-caps, which differ greatly from positions within helix interiors, suggest that N-caps should be treated explicitly in any consideration of helical structure in peptides or proteins.

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“…The observed distributions of amino acids for these sites in protein crystal structures is quite different for preferences for interior positions (Richardson & Richardson, 1988). The importance of capping for helix structure and stability has been studied in peptide (Nicholson et al, 1988(Nicholson et al, , 1991Fairman et al, 1989;Bruch et al, 1991;Lyu et al, 1992Lyu et al, , 1993Chakrabartty et al, 1993a; 1326Forood et al, 1993, 1994Heinz et al, 1993;Regan, 1993;Doig et al, 1994;Zhou et al, 1994aZhou et al, , 1994b and protein systems (Serran0 & Fersht, 1989;Lecomte& Moore, 1991;Bell et al, 1992; Serrano et al, 1992b;Harper & Rose, 1993;Kaarsholm et al, 1993; Zhukovsky et al, 1994).Although several groups have measured the free energy changes that arise when certain residues are substituted at capping positions (see below), many amino acids have not been investigated at all. In this paper, we determine the intrinsic preferences for both N-and C-cap positions in our a-helical model peptide for all 20 naturally occurring amino acids in various charged states, plus the N-terminal acetyl and C-terminal amide groups.…”

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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 stop signals in proteins and peptides: The capping box

Cited by 340 publications

References 36 publications

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Structures of N‐termini of helices in proteins

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

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