Stabilization of α-Helices by Dipole−Dipole Interactions within α-Helices

Park, Changmoon; Goddard, William A.

doi:10.1021/jp0001743

Cited by 41 publications

(55 citation statements)

References 34 publications

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“…Previous studies analyzed the relative helix versus -strand stability based on polyglycine 13 or pAla [18][19][20] peptides. The influence of single amino acid replacements in glycine pentapeptides 21 on helix stability were also studied, using mixed QM/semiempirical calculations (DFT/AM1).…”

Section: Stability Of the Helix Versus Extended Conformations In Reprmentioning

confidence: 99%

Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

Jagielska

Skolnick

2007

J Comput Chem

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Current all-atom force fields often fail to recognize the native structure of a protein as the lowest free energy minimum. One possible cause could be the mathematical form of the potential based on the assumption that the conformation of a residue is independent of its neighbors. Here, using quantum mechanical (QM) methods (MP2/6-31g**//HF/6-31g** and MP2/cc-pVDZ//cc-pVDZ//HF/cc-pVDZ), the intrinsic correctness of the gas phase terms (without solvation) of the Amber ff03 and ff99 potentials are examined by testing their ability to reproduce the relative 3 10 -helix versus extended structure stabilities in the gas phase for 1-7-residue alanine, valine, leucine, and isoleucine homopolypeptides. The 3 10 -helix versus extended state stability strongly depends on chain length and less on the amino acid identity. The helical conformation becomes lower in energy than the extended conformation for all tested peptides longer than two residues, and its stability increases with the increase of chain length. The ff03 potential better describes the 3 10 -helix versus extended state energy than ff99 and also reproduces the curvature of the relative helix-extended state energies. Therefore, the mathematical form of the Amber potential is sufficient to describe the local effect of 3 10 -helix versus extended structure stabilization in the gas phase. However, the energy curves are shifted and the backbone geometries differ compared with the QM results. This may cause significant geometric discrepancies between native and predicted structures. Therefore, extant molecular mechanics force fields, such as Amber, need refinement of their parameters to correctly describe helix-extended state energetics and geometry of major conformations.

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Section: Stability Of the Helix Versus Extended Conformations In Reprmentioning

confidence: 99%

Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

Jagielska

Skolnick

2007

J Comput Chem

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“…41 for a recent treatment). If the peptide H-bond can be represented by peptide dipoles, then it is logical to use an electrostatic approach to analyze the solvation free energy associated with the dipoles.…”

Section: Reflections: Energetics Of Peptide H-bondsmentioning

confidence: 99%

In Search of the Energetic Role of Peptide Hydrogen Bonds

Baldwin

2003

Journal of Biological Chemistry

123

102

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Forming peptide hydrogen bonds was considered to be probably the most important driving force for protein folding in 1951, when Linus Pauling and Robert Corey proposed the hydrogenbonded structures of the ␣-helix (1) and two ␤-sheets (2). Because the peptide CO and NH groups form competing hydrogen bonds (H-bonds) to water when a protein is unfolded it was evident, however, that the net contribution of the peptide H-bond (CO⅐⅐⅐HN) to protein stability might be small. In 1955 John Schellman (3, 4) made a first analysis of the energetics of peptide H-bonds in protein folding reactions. He listed the factors that should affect the stability of a peptide ␣-helix in water, and he estimated the strength of the peptide H-bond in water by attributing the unusual thermodynamics of aqueous urea solutions (which had been measured accurately) to H-bonded urea dimers. His analysis indicated that a peptide helix in water should have at most marginal stability. Any observable helix formation should be driven by the net enthalpy change (⌬H) of forming the peptide H-bond in water, and the aqueous urea data gave ⌬H ϭ Ϫ1.5 kcal/mol. The proposal of Schellman that helix formation should be driven by the enthalpy of the peptide H-bond was adopted by Zimm and Bragg (5) and by Lifson and Roig (6) in their treatments of the statistical mechanics of helix formation. Klotz and Franzen (7) found, however, that the dimerization of N-methylacetamide (NMA) in water was too small to measure, and the energetic significance of peptide H-bonds for protein folding lapsed into uncertainty. Interest in the problem diminished further as support grew for the bold proposal by Walter Kauzmann (8) in 1959 that the hydrophobic interaction provides the major driving force for protein folding. Hydrogen Bond InventoryThe change in internal energy (⌬E) for forming a hydrogen bond in the gas phase can be calculated by quantum mechanics, and with steady improvement in methods of calculation, calculated values of H-bond energies are now believed to be comparable in accuracy to good experimental values. A recent calculated value for the ⌬E of dimerization of NMA in vacuum is Ϫ6.6 kcal/mol, which has been used as a model for the peptide H-bond (9). Some older calculated values indicate that the H-bonds formed by amide CO and NH groups to water (W), and also the W⅐⅐⅐W and CO⅐⅐⅐NH H-bonds, have roughly equal energies of about Ϫ6 Ϯ 1 kcal/mol (10, 11). The conclusion a decade ago was that a hydrogen bond inventory, discussed by Alan Fersht (12, 13), is sufficient to describe the net enthalpy of the peptide H-bond in water. In writing the inventory, the number of H-bonds is assumed to be the same, whereas their types are similar on both sides of the equation.If the assumptions made in writing Equation 1 are valid, then the net enthalpy of the peptide H-bond in water is 0 Ϯ 1 kcal/mol to a first approximation. In making quantum mechanics calculations to model the peptide H-bond and the NH⅐⅐⅐W and CO⅐⅐⅐W H-bonds, the energies

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“…[19] In this context, it is also increasingly appreciated that the structural features that cause peptides to adopt secondary structures (including bturns) are complex. In addition to hydrogen bonding, [20] allylic strain about the Pro-d-Val amide, [21] dipole neutralization of the Pro-d-Val carbonyl, [22] and n-to-p* donation [23] from the Xaa-Pro carbonyl lone pair to the Pro-Yaa carbonyl may each contribute to the b-turns stability.…”

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confidence: 99%

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

2008

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Keywordsepoxidation; peptide; asymmetric catalysis; olefin isostere; fluorine; peptidomimetic The biosynthesis of natural products that contain epoxides represents a powerful stimulus for the study of "epoxidase" enzymes. [i] Likewise, these processes have inspired a generation of science focused on small molecule catalysts that mediate selective epoxidations through a variety of mechanisms. [ii] With respect to the naturally occurring epoxidases, the mechanistic basis of O-atom transfer is often associated with the chemistry of either flavinoid cofactors, P450 enzymes containing a heme group, or chloroperoxidases that lead to stepwise ring formation. [iii] In thinking about the known biosynthetic apparatus for epoxide formation, we became curious about an alternative mode for O-atom transferone based on functional groups available in proteins, but perhaps not well-documented in the biosynthesis of epoxides. In particular, we speculated and recently showed that asparticacid-containing peptides (e.g., 1; Figure 1a) might shuttle between the side-chain carboxylic acid and the corresponding peracid (e.g., 2) creating a catalytic cycle competent for asymmetric epoxidation with turnover of the aspartate-derived catalyst. Such an approach is orthogonal to the Julia-Colonna epoxidation, a complementary peptide-based epoxidation based on a nucleophilic mechanism. [iv] Indeed, as shown in Figure 1b, this new electrophilic epoxidation catalytic cycle mediates the asymmetric epoxidation of substrates like 3 to give products like 4 with up to 92% ee. [v] Mechanistic questions abound in this catalytic system. To date, we have identified a number of relevant aspects. For example, we observed off-catalytic cycle intermediates, including catalytically inactive diacyl peroxides (6). [vi] We also showed that these off-cycle intermediates could be reinserted into the productive pathway through the action of nucleophiles such as DMAP or DMAP-N-oxide (7). On the other hand, the basis of stereochemical information transfer was not immediately clear. Indeed, the high precision delineation of the stereochemical mode of action of chiral catalysts is a critical frontier in the discipline of asymmetric catalysis, whether the catalysts are enzymes or small molecules. With this back-drop, we began a detailed study of the mode of action for catalyst 5.The conversion of 3 to 4 was originally undertaken with the hypothesis that substratecatalyst hydrogen bonding might contribute to transition state organization. [vii] Indeed, a substrate lacking obvious H-bonding capability (phenylcyclohexene) was found to undergo epoxidation with catalyst 5 with low enantioselectivity (~10% ee). Thus, we envisioned several potential loci for contacts between 3 and 5 (Figure 2a). Shown in blue is the site that

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Stabilization of α-Helices by Dipole−Dipole Interactions within α-Helices

Cited by 41 publications

References 34 publications

Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

In Search of the Energetic Role of Peptide Hydrogen Bonds

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

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Stabilization of α-Helices by Dipole−Dipole Interactions within α-Helices

Cited by 41 publications

References 34 publications

Origin of intrinsic 310‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

Origin of intrinsic 310‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

In Search of the Energetic Role of Peptide Hydrogen Bonds

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

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Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field

Origin of intrinsic 3₁₀‐helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field