scholarly journals Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control

2020 ◽  
Vol 11 (36) ◽  
pp. 9950-9961
Author(s):  
Rajeev Ramanan ◽  
Shobhit S. Chaturvedi ◽  
Nicolai Lehnert ◽  
Christopher J. Schofield ◽  
Tatyana G. Karabencheva-Christova ◽  
...  
Keyword(s):  
Molecular Orbital ◽  
Active Site ◽  
Histone Demethylase ◽  
Orbital Control ◽  
Correlated Motions ◽  
Correlated Motion

The second sphere residues and regions of the protein in histone demethylase enzymes that makes correlated motion with the active site contribute to efficient catalysis.

scholarly journals Interactive design and synthesis of a novel antibacterial agent

1994 ◽  
Vol 72 (4) ◽  
pp. 1051-1065 ◽  
Author(s):  
Saul Wolfe ◽  
Haolun Jin ◽  
Kiyull Yang ◽  
Chan-Kyung Kim ◽  
Ernest McEachern
Keyword(s):  
Molecular Orbital ◽  
Active Site ◽  
Antibacterial Agent ◽  
De Novo ◽  
Three Dimensional ◽  
Hydroxyl Group ◽  
Molecular Orbital Calculations ◽  
Binding Studies ◽  
Molecular Mechanics Calculations ◽  
Substrate Complex

β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e, fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (G1) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme–substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure–reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (−ΔE > 10 kcal/mol). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D- and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.

scholarly journals Computational Analysis of Dynamic Allostery and Control in the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Igors Dubanevics ◽  
Tom C.B. McLeish
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Competitive Inhibition ◽  
Vital Role ◽  
Dynamical Structure ◽  
Elastic Network Model ◽  
Correlated Motions ◽  
Main Protease ◽  
Candidate Regions ◽  
Novel Coronavirus

AbstractThe COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic and no vaccine or antiviral drugs exist at the moment of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition which targets regions beyond the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an Elastic Network Model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse the dynamics and thermodynamics of the main protease’s ENM. We found a rich and heterogeneous dynamical structure in the correlated motions, including allosterically correlated motions between the homodimeric protease’s active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site for control of the protease function. Our results suggest new dynamically-driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragmentbased binding screens. The results also provide new insight into the protein physics of fluctuation allostery and its underpinning dynamical structure.

Ultrafast electron dynamics as a route to explore chemical processes

2019 ◽  
pp. 343-366
Author(s):  
Alexander I. Kuleff
Keyword(s):  
Molecular Orbital ◽  
Electron Correlation ◽  
Time Scale ◽  
Chemical Reactivity ◽  
Chemical Processes ◽  
Electron Dynamics ◽  
Charge Migration ◽  
Migration Dynamics ◽  
Correlated Motion ◽  
Femtosecond Time Scale

These lecture notes give a concise overview of the problem of describing quantum-mechanically the correlated motion of electrons and nuclei in a molecule. The focus is put on the methodology allowing to study the ultrafast, pure electron dynamics triggered by ionization of a molecule. It is shown that due to the electron correlation the removal of an electron from a molecular orbital can create electronic coherences manifesting in the migration of the positive charge throughout the system on a few-femtosecond time scale; a phenomenon known as correlation-driven charge migration. Some interesting perspectives for designing schemes to influence the chemical reactivity of the molecule by manipulating the charge migration dynamics are also briefly discussed.

scholarly journals Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

2015 ◽  
Vol 21 (52) ◽  
pp. 18869-18869
Author(s):  
Wilian A. Cortopassi ◽  
Robert Simion ◽  
Charles E. Honsby ◽  
Tanos C. C. França ◽  
Robert S. Paton
Keyword(s):  
Active Site ◽  
Histone Demethylase ◽  
Protein Environment
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