Conformer Profiles and Biological Activities of Peptides

Payne, John W.; Marshall, N. Justin; Grail, Barry M.; Gupta, Sona

doi:10.2174/1385272023373428

Cited by 15 publications

(7 citation statements)

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“…In design of peptides, the peptide flexibility is often reduced by the introduction of stereochemically constrained residues such as the proline and phenylalanine residues (Payne et al, 2002). MD simulation results of models without fixed residues observed in Set 1 agree with the lower degrees of flexibilities expected for the FPYVAE and FFYVAE peptides.…”

Section: Peptide Designsupporting

confidence: 53%

“…The correlation between the conformational flexibility and bioactivity has been already examined in many studies (Pierschbacher and Ruoslahti, 1987;Becker et al, 2000;Payne et al, 2002). According to the conformational aspect, the binding affinity is defined as the percentage of overlap between a predefined set of conformations that can fit the binding site and the actual set of conformations that the molecule can adopt (Becker, 1997;Becker et al, 2000).…”

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confidence: 99%

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Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG‐CoA reductase

Pak

Koo

Kim

et al. 2008

J of Molecular Recognition

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This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC(50) = 0.4 microM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC(50) = 484 microM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides.

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Section: Peptide Designsupporting

confidence: 53%

mentioning

confidence: 99%

Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG‐CoA reductase

Pak

Koo

Kim

et al. 2008

J of Molecular Recognition

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“…A conformational analysis revealed the existence of a 'turn' structure in these peptide sequences (Pak et al, 2004). Based on these presuppositions, the maintained conformation close to the bioactive conformations of VPTG and VPGE fragments in the design of a competitive inhibitor for HMGR was the focus of this study through a number of peptides, which were designed using a conformational aspect of a structure-based approach (Valero et al, 2000;Payne et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Recognized sequence and conformation in design of linear peptides as a competitive inhibitor for HMG‐CoA reductase

Pak

Koo

Yun

et al. 2007

J of Molecular Recognition

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This study is an attempt to develop a simple search method for lead peptide candidates, which include constrained structures in a recognized sequence, using the design of a competitive inhibitor for HMG-CoA reductase (HMGR). A structure-functional analysis of previously synthesized peptides proposes that a competitive inhibitory peptide can be designed by maintaining bioactive conformation in a recognized sequence. A conformational aspect of the structure-based approach was applied to the peptide design. By analysis of the projections obtained through a principle component analysis (PCA) for short linear and cyclic peptides, a head-to-tail peptide cycle is considered as a model for its linear analogy. It is proposed that activities of the linear peptides based on an identical amino acid sequence, which are obtained from a less flexible peptide cycle, would be relatively higher than those obtained from more flexible cyclic peptides. The design criterion was formulated in terms of a 'V' parameter, reflecting a relative deviation of an individual peptide cycle from an average statistical peptide cycle based on all optimized structures of the cyclic peptides in set. Twelve peptide cycles were selected for the peptide library. Comparing the calculated 'V' parameters, two cyclic peptides (GLPTGG and GFPTGG) were selected as lead cycles from the library. Based on these sequences, six linear peptides obtained by breaking the cycle at different positions were selected as lead peptide candidates. The linear GFPTGG peptide, showing the highest inhibitory activity against HMGR, increases the inhibitory potency nearly tenfold. Kinetic analysis reveals that the GFPTGG peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K(i)) of 6.4 +/- 0.3 microM. Conformational data support a conformation of the designed peptides close to the bioactive conformation of the previously synthesized active peptides.

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“…This involves a zwitterionic peptide, where CO 2 − of the C-terminus (or a carboxylic acid side chain) coordinates to Cr(III) in a manner similar to structure A of Figure 2, where two aqua ligands are lost prior to glycine binding. Peptides are known to exist in solution as zwitterions 81 and calculations on several small peptides have shown that their gas-phase species are zwitterionic at low charge states. 70,82,83 Production of [Cr-(peptide)(H 2 O) 4 ] 3+ could occur in solution or in the gas phase; it might also involve a lesser number of aqua ligands than four.…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

Mechanistic Study of Enhanced Protonation by Chromium(III) in Electrospray Ionization: A Superacid Bound to a Peptide

Persaud

Dieke

Jing

et al. 2019

J. Am. Soc. Mass Spectrom.

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Addition of trivalent chromium, Cr(III), to solutions undergoing electrospray ionization (ESI) enhances protonation and leads to formation of [M + 2H]2+ for peptides that normally produce [M + H]+. This effect is explored using electronic structure calculations at the density functional theory (DFT) level to predict the energetics of various species that are potentially important to the mechanism. Gas- and solution-phase reaction free energies for glycine and its anion reacting with [Cr(III)(H2O)6]3+ and for dehydration of these species have been predicted, where glycine is used as a simple model for a peptide. For comparison, calculations were also performed with Fe(III), Al(III), Sc(III), Y(III), and La(III). Removal of water from these complexes, as would occur during the ESI desolvation process, results in species that are highly acidic. The calculated pK a of Cr(III) with a single solvation shell is −10.8, making [Cr(III)(H2O)6]3+ a superacid that is more acidic than sulfuric acid (pK a = −8.8). Binding to glycine requires removal of two aqua ligands, which gives [Cr(III)(H2O)4]3+ that has an extremely acidic pK a of −28.8. Removal of additional water further enhances acidity, reaching a pK a of −84.7 for [Cr(III)(H2O)]3+. A mechanism for enhanced protonation is proposed that incorporates computational and experiment results, as well as information on the known chemistry of Cr(III), which is substitutionally inert. The initial step involves binding of [Cr(III)(H2O)4]3+ to the deprotonated C-terminus of a peptide. As the drying process during ESI strips water from the complex, the resulting superacid transfers protons to the bound peptide, eventually leading to formation of [M + 2H]2+.

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Conformer Profiles and Biological Activities of Peptides

Cited by 15 publications

References 0 publications

Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG‐CoA reductase

Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG‐CoA reductase

Recognized sequence and conformation in design of linear peptides as a competitive inhibitor for HMG‐CoA reductase

Mechanistic Study of Enhanced Protonation by Chromium(III) in Electrospray Ionization: A Superacid Bound to a Peptide

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