Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins?

Winkler, David A.; Katz, Ira; Farjot, Géraldine; Warden, Andrew C.; Thornton, Aaron W.

doi:10.1002/cmdc.201800434

Cited by 9 publications

(18 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous validation study showed that in silico methods can accurately predict the binding sites of noble gases in proteins. Our methods recapitulated 399 experimental noble gases binding positions in 133 diverse proteins with accuracies between 97 and 100% . We found 94% of all the crystallographic xenon atoms were within 1 Xe van der Waals (VdW) diameter of a predicted binding site and 97% lay within 2 VdW diameters.…”

Section: Introductionmentioning

confidence: 82%

“…In these calculations, we assumed that removal of water and other solvents from the experimental structures would not affect the noble gas binding calculations. This is based on the results of the validation study where 399 experimental noble gas binding sites were correctly identified using the same assumption. Noble gases tend to be lipophilic and have low water solubility …”

Section: Methodsmentioning

confidence: 99%

“…This is based on the results of the validation study where 399 experimental noble gas binding sites were correctly identified using the same assumption. Noble gases tend to be lipophilic and have low water solubility …”

Section: Methodsmentioning

confidence: 99%

“…It is obvious that such an undertaking is only feasible and sensible if we have a high degree of confidence that computational methods can predict the binding interactions of noble gases with diverse proteins accurately. Given the simplicity of the ligands (single atoms with limited properties), we and others − have shown that the binding site location and interaction energy of noble gases in proteins can be predicted with good accuracy. Our previous validation study showed that in silico methods can accurately predict the binding sites of noble gases in proteins.…”

Section: Introductionmentioning

confidence: 91%

See 3 more Smart Citations

Massive in Silico Study of Noble Gas Binding to the Structural Proteome

Winkler

Warden

Prangé

et al. 2019

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas–protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas–protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop “atomic drugs” that can fully exploit their considerable and relatively unexplored potential in medicine.

show abstract

Section: Introductionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

See 2 more Smart Citations

Massive in Silico Study of Noble Gas Binding to the Structural Proteome

Winkler

Warden

Prangé

et al. 2019

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The accuracy of the numerical approach has been validated on existing crystallographic structures of proteins in complex with noble gases. 29 The results of a docking calculations consist of a potential binding energy for all locations around the protein based on a 0.3 Å computational grid. From these thousands of potential binding sites, the 20 most likely, based on their gas binding energy, have been selected for ranking.…”

Section: Introductionmentioning

confidence: 99%

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families

Hammami

Farjot

Naveau

et al. 2022

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Argon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modelling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify amongst all predicted noble gas binding sites, the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins, the conserved binding sites whose shape, localization, hydrophobicity and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that amongst the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy correspond to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation.

show abstract

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

et al. 2022

View full text Add to dashboard Cite

The intermolecular interactions of noble gases in biological systems are associated with numerous biochemical responses, including apoptosis, inflammation, anesthesia, analgesia, and neuroprotection. The molecular modes of action underlying these responses are largely unknown. This is in large part due to the limited experimental techniques to study protein–gas interactions. The few techniques that are amenable to such studies are relatively low-throughput and require large amounts of purified proteins. Thus, they do not enable the large-scale analyses that are useful for protein target discovery. Here, we report the application of stability of proteins from rates of oxidation (SPROX) and limited proteolysis (LiP) methodologies to detect protein–xenon interactions on the proteomic scale using protein folding stability measurements. Over 5000 methionine-containing peptides and over 5000 semi-tryptic peptides, mapping to ∼1500 and ∼950 proteins, respectively, in the yeast proteome, were assayed for Xe-interacting activity using the SPROX and LiP techniques. The SPROX and LiP analyses identified 31 and 60 Xe-interacting proteins, respectively, none of which were previously known to bind Xe. A bioinformatics analysis of the proteomic results revealed that these Xe-interacting proteins were enriched in those involved in ATP-driven processes. A fraction of the protein targets that were identified are tied to previously established modes of action related to xenon’s anesthetic and organoprotective properties. These results enrich our knowledge and understanding of biologically relevant xenon interactions. The sample preparation protocols and analytical methodologies developed here for xenon are also generally applicable to the discovery of a wide range of other protein–gas interactions in complex biological mixtures, such as cell lysates.

show abstract

Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins?

Cited by 9 publications

References 39 publications

Massive in Silico Study of Noble Gas Binding to the Structural Proteome

Massive in Silico Study of Noble Gas Binding to the Structural Proteome

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

Contact Info

Product

Resources

About