A Microscopic View of Helix Propagation: N and C-terminal Helix Growth in Alanine Helices

Young, William S.; Brooks, Charles L.

doi:10.1006/jmbi.1996.0339

Cited by 121 publications

(169 citation statements)

References 41 publications

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“…One can rationalize this observation in terms of the solvation preference of both termini; carbonyl groups at the C terminus have larger dipole moments and thus desolvation is disfavored compared with the amide groups of the N terminus. This argument is consistent with previous experimental and theoretical studies indicating that helical stability is greater at the N terminus than the C terminus (36).…”

Section: Resultssupporting

confidence: 93%

Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations

Brooks

2005

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

172

209

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The mechanism of interfacial folding and membrane insertion of designed peptides is explored by using an implicit membrane generalized Born model and replica-exchange molecular dynamics. Folding͞insertion simulations initiated from fully extended peptide conformations in the aqueous phase, at least 28 Å away from the membrane interface, demonstrate a general mechanism for structure formation and insertion (when it occurs). The predominately hydrophobic peptides from the synthetic WALP and TMX series first become localized at the membrane-solvent interface where they form significant helical secondary structure via a helix-turn-helix motif that inserts the central hydrophobic residues into the membrane interior, and then fluctuations occur that provide a persistent helical structure throughout the peptide and it inserts with its N-terminal end moving across the membrane. More specifically, we observed that: (i) the WALP peptides (WALP16, WALP19, and WALP23) spontaneously insert in the membrane as just noted; (ii) TMX-1 also inserts spontaneously after a similar mechanism and forms a transmembrane helix with a population of Ϸ50% at 300 K; and (iii) TMX-3 does not insert, but exists in a fluctuating membrane interface-bound form. These findings are in excellent agreement with available experimental data and demonstrate the potential for new implicit solvent͞ membrane models together with advanced simulation protocols to guide experimental programs in exploring the nature and mechanism of membrane-associated folding and insertion of biologically important peptides.implicit solvation ͉ replica-exchange molecular dynamics ͉ TMX-1 ͉ TMX-3 ͉ WALP B iological membranes provide a unique hydrophilic and hydrophobic environment in which a protein may undergo a thermodynamically driven conformational transition from a water-soluble form to a membrane-bound state (1-3). Membrane insertion is a key process in the biological functioning of peptides and proteins such as bacterial toxins (4), antimicrobial peptides (5), and fusion peptides (6). Because of the importance of the processes of membrane association and insertion to our understanding of function in these systems, it is essential to understand the thermodynamic balance between the watersoluble state and the membrane-bound state.The conformational and energetic changes of these peptides͞ proteins at the molecular level during the spontaneous insertion process, generally, remain poorly understood. However, recent experiments using designed (synthetic) model peptides have yielded new insights into these events (6-11). However, a principal experimental difficulty in designing peptides to study spontaneous insertion arises from the insoluble and aggregationprone nature of these highly nonpolar molecules in aqueous solution (8,11). Considering the biological importance of these systems and the processes that control their functioning, modern methods from theory and computational biology should aim to assist experiments in understanding membrane insertion at the molecular leve...

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Section: Resultssupporting

confidence: 93%

Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations

Brooks

2005

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

172

209

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“…The new sequence was designed to avoid potential side-chain interactions between the guest residues (Λ) and the corresponding i + 3 position; lysine was incorporated to increase water solubility of the host. The second position was chosen for the introduction of guests because the conformation of this residue is implicated in helix induction near the N terminus (39,40). The helical conformation of ds-2A: XAKG*ASDLWKLLS was assessed using a combination of 1D NMR, total correlation spectroscopy, and rotating-frame nuclear Overhauser effect correlation spectroscopy (ROESY) studies in aqueous solutions (SI Text, Table S1, and Fig.…”

Section: Significancementioning

confidence: 99%

“…Helix-coil transitions have been previously investigated using molecular-dynamics simulations to analyze helix propensity and nucleation timescales, but, to our knowledge, the effect of point mutations on helix nucleation has not been explored systematically (28,39,49). We determined the impact of different residues on the formation of an α-turn in an acetylated and methylamidated model peptide sequence, Ac-AΛA-NHMe.…”

Section: --I----------------(2i)mentioning

confidence: 99%

Effects of side chains in helix nucleation differ from helix propagation

Miller

Watkins

Kallenbach

et al. 2014

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

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Helix-coil transition theory connects observable properties of the α-helix to an ensemble of microstates and provides a foundation for analyzing secondary structure formation in proteins. Classical models account for cooperative helix formation in terms of an energetically demanding nucleation event (described by the σ constant) followed by a more facile propagation reaction, with corresponding s constants that are sequence dependent. Extensive studies of folding and unfolding in model peptides have led to the determination of the propagation constants for amino acids. However, the role of individual side chains in helix nucleation has not been separately accessible, so the σ constant is treated as independent of sequence. We describe here a synthetic model that allows the assessment of the role of individual amino acids in helix nucleation. Studies with this model lead to the surprising conclusion that widely accepted scales of helical propensity are not predictive of helix nucleation. Residues known to be helix stabilizers or breakers in propagation have only a tenuous relationship to residues that favor or disfavor helix nucleation.synthetic helices | helix propensity T he α-helix is the most prevalent secondary structure in proteins and can form extremely rapidly. Helix formation is thus crucial in early steps of protein folding, and a complete description of the kinetics and thermodynamics of α-helix formation is fundamental for understanding protein folding (1). Theoretical models of the helix-coil transition consider helix formation to proceed in two steps: initial nucleation of a helical sequence, denoted by the parameter σ in the Zimm-Bragg notation (2), followed by more favorable helix propagation, denoted by s parameters. This distinction identifies the energetically unfavorable organization of three consecutive amino acid residues to form a helical nucleus as the slow step in helix formation (2-4). Helix propagation, in contrast, refers to the addition of the next hydrogen bond to a preformed helix (Fig. 1A). Zimm-Bragg or equivalent theories posit that formation of short peptide helices in water is unfavorable because the large decrease in entropy required for nucleation is not adequately compensated by the enthalpic gain from forming a small number of hydrogen bonds.The ability of different peptide sequences to adopt helical conformations has been rigorously investigated, and the stability of α-helices can be estimated from widely used scales of helical propensity (5). These scales are important for our understanding of protein structure, folding, and function. The classical studies for determination of helix propensities have used peptides, coiled-coils, and protein models for host-guest studies in which a guest residue is systematically substituted at a site in a host structure (6-12). Helix-coil transition theory then relates changes in the conformational stability to microscopic helix propensities or s constants for individual residues. The results provide a quantitative basis for evaluating t...

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“…For example, Young and Brooks have performed MD simulations with umbrella sampling on a series of Ala peptides and found that the microscopic helix propagation parameters of the residues at the N-terminus depend strongly on the length of the -helix. 54 Using a unique end-capping group, Ac-Hel, which is also a helicity reporter through its distinct 1 H NMR t/c ratio, Kemp and co-workers 1 have measured the helicities of a series of peptides and proposed that the helical propensity of Ala is length dependent. For example, they showed that at 2 °C Ala's helical propensity is 1.03 for peptides with 6 residues, but for peptides of longer than 10 residues, Ala's helical propensity increases to 1.26.…”

Section: Length-dependent T-jump Relaxation Kineticsmentioning

confidence: 99%

Length Dependent Helix−Coil Transition Kinetics of Nine Alanine-Based Peptides

et al. 2004

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It is well-known that end caps and the peptide length can dramatically influence the thermodynamics of the helix-coil transition. However, their roles in determining the kinetics of the helix-coil transition have not been studied extensively and are less well understood. Kinetic Ising models and sequential kinetic models involving barrier crossing via diffusion all predict that the helix formation time depends monotonically on the peptide length with the relaxation time increasing with respect to increasing chain length. Here, we have studied the helix-coil transition kinetics of a series of Ala-based -helical peptides of different length (19-39 residues), with and without end caps, using time-resolved infrared spectroscopy coupled with laser-induced temperature jump (T-jump) initiation method. The helical content of these peptides was kinetically monitored by probing the amide carbonyl stretching frequencies (i.e., the amide I band) of the peptide backbone. We found that the relaxation rates for peptides with efficient end caps are more rapid than those of the corresponding peptides without good end caps. These results indicate that efficient end-capping sequences can not only stabilize preexisting helices but also promote helix formation through initiation. Furthermore, we found that the relaxation times of these peptides, following a T-jump of 1-11 °C, show rather complex behaviors as a function of the peptide length, in disagreement with theoretical predications. Theses results are not readily explained by theories in which Ala is taken to have a single helical propensity (s). However, recent studies have suggested that s depends on chain length; when this factor is considered, the mean first-passage times of the coil-to-helix transition show similar dependence on the peptide length as those observed experimentally.

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A Microscopic View of Helix Propagation: N and C-terminal Helix Growth in Alanine Helices

Cited by 121 publications

References 41 publications

Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations

Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations

Effects of side chains in helix nucleation differ from helix propagation

Length Dependent Helix−Coil Transition Kinetics of Nine Alanine-Based Peptides

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