Theoretical Insights into the mechanism of selective peptide bond hydrolysis catalyzed by [Pd(H2O)4]2+

Amit Kumar, Xiaoxia Zhu, Kathryn Walsh, Rajeev Prabhakar

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In this study, mechanisms for the hydrolysis of the Gly-Pro bond in Gly-Pro-Met and Gly-Pro-His, the Gly-Sar bond in Gly-Sar-Met, and the Gly-Gly bond In the Gly-Gly-Met peptide catalyzed by [Pd(H2O) 4]2+ (I) have been investigated at the DFT level. In all cases, the optimized structure of the active bidentate complex, formed by the reaction of I with the substrate [Pd(H2O)2{(Gly)-(Pro)- (Met-ΚS, ΚN)}]1+ complex for the Gly-Pro-Met peptide, was found to exist In the trans conformation. This structure is In agreement with the experimentally measured TOCSY and ROESY 1H NMR spectra. After the formation of this complex, the following two mechanisms have been proposed experimentally: (1) external attack mechanism and (2) Internal delivery mechanism. The DFT calculations suggest that in the external attack mechanism the calculated barriers are prohibitively high (i.e., 50-70 kcal/mol) for the cleavage of all the peptide bonds, and therefore, this mechanism Is ruled out. However, In the internal delivery mechanism, the bidentate complex is first transformed from the trans to the cis conformation. Here, the overall barriers for the hydrolysis of the Gly-ProMet, Gly-Pro-His, Gly-Sar-Met, and Gly-Gly-Met peptide bonds are 38.3,41.4,39.8, and 39.2 kcal/mol, respectively. These barriers are In much better agreement with the experimentally measured rate constants at pH 2.0 and at 60 °C. The substitution of Pd(II) with Pt(II) was found to make a negligibly small difference (0.53 kcal/mol) on the barrier for the cleavage of the Gly-Pro-His bond. These calculations Indicate that after the creation of the active bidentate complex in the trans conformation the Internal delivery mechanism Is the most energetically feasible.

Original languageEnglish
Pages (from-to)38-46
Number of pages9
JournalInorganic Chemistry
Volume49
Issue number1
DOIs
StatePublished - Jan 4 2010

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peptides
hydrolysis
Hydrolysis
Conformations
Peptides
Discrete Fourier transforms
Promethazine
delivery
attack
cleavage
Rate constants
Substitution reactions
Nuclear magnetic resonance
Substrates
glycylsarcosine
substitutes
nuclear magnetic resonance

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Physical and Theoretical Chemistry

Cite this

Theoretical Insights into the mechanism of selective peptide bond hydrolysis catalyzed by [Pd(H2O)4]2+. / Kumar, Amit; Zhu, Xiaoxia; Walsh, Kathryn; Prabhakar, Rajeev.

In: Inorganic Chemistry, Vol. 49, No. 1, 04.01.2010, p. 38-46.

Research output: Contribution to journalArticle

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abstract = "In this study, mechanisms for the hydrolysis of the Gly-Pro bond in Gly-Pro-Met and Gly-Pro-His, the Gly-Sar bond in Gly-Sar-Met, and the Gly-Gly bond In the Gly-Gly-Met peptide catalyzed by [Pd(H2O) 4]2+ (I) have been investigated at the DFT level. In all cases, the optimized structure of the active bidentate complex, formed by the reaction of I with the substrate [Pd(H2O)2{(Gly)-(Pro)- (Met-ΚS, ΚN)}]1+ complex for the Gly-Pro-Met peptide, was found to exist In the trans conformation. This structure is In agreement with the experimentally measured TOCSY and ROESY 1H NMR spectra. After the formation of this complex, the following two mechanisms have been proposed experimentally: (1) external attack mechanism and (2) Internal delivery mechanism. The DFT calculations suggest that in the external attack mechanism the calculated barriers are prohibitively high (i.e., 50-70 kcal/mol) for the cleavage of all the peptide bonds, and therefore, this mechanism Is ruled out. However, In the internal delivery mechanism, the bidentate complex is first transformed from the trans to the cis conformation. Here, the overall barriers for the hydrolysis of the Gly-ProMet, Gly-Pro-His, Gly-Sar-Met, and Gly-Gly-Met peptide bonds are 38.3,41.4,39.8, and 39.2 kcal/mol, respectively. These barriers are In much better agreement with the experimentally measured rate constants at pH 2.0 and at 60 °C. The substitution of Pd(II) with Pt(II) was found to make a negligibly small difference (0.53 kcal/mol) on the barrier for the cleavage of the Gly-Pro-His bond. These calculations Indicate that after the creation of the active bidentate complex in the trans conformation the Internal delivery mechanism Is the most energetically feasible.",
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AB - In this study, mechanisms for the hydrolysis of the Gly-Pro bond in Gly-Pro-Met and Gly-Pro-His, the Gly-Sar bond in Gly-Sar-Met, and the Gly-Gly bond In the Gly-Gly-Met peptide catalyzed by [Pd(H2O) 4]2+ (I) have been investigated at the DFT level. In all cases, the optimized structure of the active bidentate complex, formed by the reaction of I with the substrate [Pd(H2O)2{(Gly)-(Pro)- (Met-ΚS, ΚN)}]1+ complex for the Gly-Pro-Met peptide, was found to exist In the trans conformation. This structure is In agreement with the experimentally measured TOCSY and ROESY 1H NMR spectra. After the formation of this complex, the following two mechanisms have been proposed experimentally: (1) external attack mechanism and (2) Internal delivery mechanism. The DFT calculations suggest that in the external attack mechanism the calculated barriers are prohibitively high (i.e., 50-70 kcal/mol) for the cleavage of all the peptide bonds, and therefore, this mechanism Is ruled out. However, In the internal delivery mechanism, the bidentate complex is first transformed from the trans to the cis conformation. Here, the overall barriers for the hydrolysis of the Gly-ProMet, Gly-Pro-His, Gly-Sar-Met, and Gly-Gly-Met peptide bonds are 38.3,41.4,39.8, and 39.2 kcal/mol, respectively. These barriers are In much better agreement with the experimentally measured rate constants at pH 2.0 and at 60 °C. The substitution of Pd(II) with Pt(II) was found to make a negligibly small difference (0.53 kcal/mol) on the barrier for the cleavage of the Gly-Pro-His bond. These calculations Indicate that after the creation of the active bidentate complex in the trans conformation the Internal delivery mechanism Is the most energetically feasible.

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