Theoretical Studies of the Acid–Base Equilibria in a Model Active Site of the Human 20S Proteasome

2021 ◽  
Vol 61 (4) ◽  
pp. 1942-1953
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
20S Proteasome ◽  
Theoretical Studies ◽  
Acid Base

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

scholarly journals The catalase–hydrogen peroxide system. A theoretical appraisal of the mechanism of catalase action

1968 ◽  
Vol 110 (4) ◽  
pp. 621-629 ◽  
Author(s):  
Peter Jones ◽  
A. Suggett
Keyword(s):  
Active Site ◽  
Molecular Level ◽  
Molecular Model ◽  
Experimental Information ◽  
Theoretical Studies ◽  
Reactive Intermediate ◽  
Acid Base ◽  
System A ◽  
Formal Mechanism ◽  
Base Functions

1. The mechanisms of catalase action advanced by Jones & Wynne-Jones (1962) and by Nicholls (1964) are compared in terms of their relative plausibilities and their utility for extension to accommodate more recent experimental information. 2. A revised formal mechanism is advanced that avoids the less satisfactory features of these mechanisms and attempts to account for the roles of catalase sub-units in both reversible and irreversible deactivation phenomena. 3. Theoretical studies of the redox chemistry of peroxides are used to provide the basis for a discussion of the mechanism of the redox act in catalatic action at the molecular level. It is suggested that an important feature of catalase action may be a mediation of the formation of a reactive intermediate by stereospecifically located acid–base functions in the active site. 4. A more detailed statement of this concept is attempted in terms of a hypothetical partial molecular model for the composition and stereochemistry of the active site of catalase. The utility of this model in describing the catalatic and peroxidatic actions of catalase is assessed.

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

scholarly journals Novel hydrogen chemisorption properties of amorphous ceramic compounds consisting of p-block elements: exploring Lewis acid-base Al–N pair site formed in-situ within polymer-derived silicon-aluminum-nitrogen-based system

2021 ◽  
Author(s):  
Shotaro Tada ◽  
Norifumi Asakuma ◽  
Shiori Ando ◽  
Toru Asaka ◽  
Yusuke Daiko ◽  
...  
Keyword(s):  
Lewis Acid ◽  
Active Site ◽  
Hydrogen Chemisorption ◽  
Acid Base ◽  
Polymer Derived Ceramics ◽  
System P ◽  
Ceramic Compounds ◽  
The Relationship

This paper reports on the relationship between the H2 chemisorption properties and reversible structural reorientation of the possible active site around Al formed in-situ within polymer-derived ceramics (PDCs) based on...

Theoretical studies on the magnetic interaction and reversible dioxygen binding of the active site in hemocyanin

2001 ◽  
Vol 335 (5-6) ◽  
pp. 395-403 ◽  
Author(s):  
Yu Takano ◽  
Shigehiro Kubo ◽  
Taku Onishi ◽  
Hiroshi Isobe ◽  
Yasunori Yoshioka ◽  
...  
Keyword(s):  
Active Site ◽  
Magnetic Interaction ◽  
Theoretical Studies

Experimental and Theoretical Studies of Acid−Base Equilibria of Substituted 4-NitropyridineN-Oxides

2003 ◽  
Vol 107 (32) ◽  
pp. 6293-6300 ◽  
Author(s):  
Joanna Berdys ◽  
Mariusz Makowski ◽  
Monika Makowska ◽  
Aniela Puszko ◽  
Lech Chmurzyński
Keyword(s):  
Theoretical Studies ◽  
Acid Base ◽  
Experimental And Theoretical Studies

Structure of the epimerization domain of tyrocidine synthetase A

2014 ◽  
Vol 70 (5) ◽  
pp. 1442-1452 ◽  
Author(s):  
Stefan A. Samel ◽  
Paul Czodrowski ◽  
Lars-Oliver Essen
Keyword(s):  
Amino Acids ◽  
Active Site ◽  
Base Catalyst ◽  
Donor Side ◽  
Acid Base ◽  
Bacillus Brevis ◽  
Peptide Synthetases ◽  
Acceptor Side ◽  
Peptide Carrier ◽  
Resolution Structure

Tyrocidine, a macrocyclic decapeptide fromBacillus brevis, is nonribosomally assembled by a set of multimodular peptide synthetases, which condense two D-amino acids and eight L-amino acids to produce this membrane-disturbing antibiotic. D-Phenylalanine, the first amino acid incorporated into tyrocidine, is catalytically derived from enzyme-bound L-Phe by the C-terminal epimerization (E) domain of tyrocidine synthetase A (TycA). The 1.5 Å resolution structure of the cofactor-independent TycA E domain reveals an intimate relationship to the condensation (C) domains of peptide synthetases. In contrast to the latter, the TycA E domain uses an enlarged bridge region to plug the active-site canyon from the acceptor side, whereas at the donor side a latch-like floor loop is suitably extended to accommodate the αIII helix of the preceding peptide-carrier domain. Additionally, E domains exclusively harbour a conserved glutamate residue, Glu882, that is opposite the active-site residue His743. This active-site topology implies Glu882 as a candidate acid–base catalyst, whereas His743 stabilizes in the protonated state a transient enolate intermediate of the L↔D isomerization.

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