What Accounts for the Different Function in Photolyases and Cryptochromes: A Computational Study of Critical Events in the Protein Active Site

2019 ◽  
Author(s):  
Daniel Holub ◽  
Thilo Mast ◽  
Tomáš Kubař ◽  
Marcus Elstner ◽  
Natacha Gillet
Keyword(s):  
Experimental Data ◽  
Proton Transfer ◽  
Molecular Mechanism ◽  
Active Site ◽  
Computational Study ◽  
Great Influence ◽  
Functional Differentiation ◽  
E Coli ◽  
Comprehensive Picture ◽  
Protein Active Site

In the current work, we present a combination of various classical and quantum computational protocols to unveil the molecular mechanism of FAD protonation in <i>E. coli</i> photolyase and its mutant. A direct comparison to our previous study on the plant cryptochrome clearly shows the great influence of the electrostatic environment and the flexibility of the FAD pocket on the proton transfer mechanism. Additionally, we propose a proton transfer pathway for WT E. coli photolyase consistent with experimental observations. Taken together, our results and previous experimental data provide a comprehensive picture about the functional differentiation in the cryptochrome-photolyase family.

What Accounts for the Different Function in Photolyases and Cryptochromes: A Computational Study of Critical Events in the Protein Active Site

2019 ◽  
Author(s):  
Daniel Holub ◽  
Thilo Mast ◽  
Tomáš Kubař ◽  
Marcus Elstner ◽  
Natacha Gillet
Keyword(s):  
Experimental Data ◽  
Proton Transfer ◽  
Molecular Mechanism ◽  
Active Site ◽  
Computational Study ◽  
Great Influence ◽  
Functional Differentiation ◽  
E Coli ◽  
Comprehensive Picture ◽  
Protein Active Site

In the current work, we present a combination of various classical and quantum computational protocols to unveil the molecular mechanism of FAD protonation in <i>E. coli</i> photolyase and its mutant. A direct comparison to our previous study on the plant cryptochrome clearly shows the great influence of the electrostatic environment and the flexibility of the FAD pocket on the proton transfer mechanism. Additionally, we propose a proton transfer pathway for WT E. coli photolyase consistent with experimental observations. Taken together, our results and previous experimental data provide a comprehensive picture about the functional differentiation in the cryptochrome-photolyase family.

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.

Isoform-Specific Destabilization of the Active Site Reveals Molecular Mechanism of Intrinsic Activation of KRas G13D

2019 ◽  
Author(s):  
Christian W. Johnson ◽  
Yi-Jang Lin ◽  
Derion Reid ◽  
Jillian Parker ◽  
Patrick Dischinger ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Active Site

WHICH IS THE PROTON-SHUTTLE IN ISOXANTHOPTERIN DEAMINASE? QM/MM MD UNDERSTANDING

2013 ◽  
Vol 12 (08) ◽  
pp. 1341002 ◽  
Author(s):  
XIN ZHANG ◽  
MING LEI
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Proton Transfer ◽  
Glutamic Acid ◽  
Active Site ◽  
Nucleophilic Attack ◽  
Zinc Ions ◽  
Initial Model ◽  
Dynamics Simulations

The deamination process of isoxanthopterin catalyzed by isoxanthopterin deaminase was determined using the combined QM(PM3)/MM molecular dynamics simulations. In this paper, the updated PM3 parameters were employed for zinc ions and the initial model was built up based on the crystal structure. Proton transfer and following steps have been investigated in two paths: Asp336 and His285 serve as the proton shuttle, respectively. Our simulations showed that His285 is more effective than Aap336 in proton transfer for deamination of isoxanthopterin. As hydrogen bonds between the substrate and surrounding residues play a key role in nucleophilic attack, we suggested mutating Thr195 to glutamic acid, which could enhance the hydrogen bonds and help isoxanthopterin get close to the active site. The simulations which change the substrate to pterin 6-carboxylate also performed for comparison. Our results provide reference for understanding of the mechanism of deaminase and for enhancing the deamination rate of isoxanthopterin deaminase.

Identification of the active site of human mitochondrial malonyl-coenzyme a decarboxylase: A combined computational study

2016 ◽  
Vol 84 (6) ◽  
pp. 792-802 ◽  
Author(s):  
Baoping Ling ◽  
Yuxia Liu ◽  
Xiaoping Li ◽  
Zhiguo Wang ◽  
Siwei Bi
Keyword(s):  
Active Site ◽  
Coenzyme A ◽  
Computational Study

Synthesis, structural characterization and cytotoxicity of a new proton transfer compound based on 2,4-diamino-1,3,5-triazine: an experimental and computational study

2021 ◽  
Author(s):  
Khodayar Gholivand ◽  
Leila Sarmadi ◽  
Nasrin Fallah ◽  
Mohammad Feraghi ◽  
Michal Dušek ◽  
...  
Keyword(s):  
Proton Transfer ◽  
Structural Characterization ◽  
Computational Study ◽  
Water Soluble ◽  
Cytotoxic Compound ◽  
Proton Transfer Compound

In the present study, a new water-soluble proton transfer cytotoxic compound (dpp)(dapt).H2O (Dx) (where dpp = diphenylphosphinate and dapt = 2,6-diamino-4-phenyl-1,3,5-triazin-1-ium ) was synthesized and characterized by IR and NMR...

Sign in / Sign up

Export Citation Format

Share Document