Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs

Ma, Chunyue; Chung, Daniel; Abramson, Dylan; Langley, David R.; Thayer, Kelly M.

doi:10.1021/acsomega.2c01289

Cited by 4 publications

(9 citation statements)

References 62 publications

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“…The method identifies a group of residues exhibiting such covariance. In addition to the PDZ system in which the method was developed and validated, it has been applied to GPX4 previously. , …”

Section: Methodsmentioning

confidence: 99%

“…In addition to the PDZ system in which the method was developed and validated, it has been applied to GPX4 previously. 66,67 H-Bond Analysis. Trajectories obtained from MD simulation were subjected to hydrogen-bond analysis in the standard implementation of the AMBER package's cpptraj suite of programs.…”

Section: ■ Methodsmentioning

confidence: 99%

“…In addition to the PDZ system in which the method was developed and validated, it has been applied to GPX4 previously. 67 , 68 …”

Section: Methodsmentioning

confidence: 99%

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Variable Regions of p53 Isoforms Allosterically Hard Code DNA Interaction

et al. 2022

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Allosteric regulation of protein activity pervades biology as the "second secret of life." We have been examining the allosteric regulation and mutant reactivation of the tumor suppressor protein p53. We have found that generalizing the definition of allosteric effector to include entire proteins and expanding the meaning of binding site to include the interface of a transcription factor with its DNA to be useful in understanding the modulation of protein activity. Here, we cast the variable regions of p53 isoforms as allosteric regulators of p53 interactions with its consensus DNA. We implemented molecular dynamics simulations and our lab's new techniques of molecular dynamics (MD) sectors and MD-Markov state models to investigate the effects of nine naturally occurring splice variant isoforms of p53. We find that all of the isoforms differ from wild type in their dynamic properties and how they interact with the DNA. We consider the implications of these findings on allostery and cancer treatment.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

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Variable Regions of p53 Isoforms Allosterically Hard Code DNA Interaction

et al. 2022

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“…Locally Thresholded Interaction Networks. The pairwise interaction energy network 32,45 is a method adopted to create representations of protein systems at the energetic level. The nodes of such networks represent the residues of the protein with edges representing the electrostatic interaction between each residue pair.…”

Section: Generation Of Interaction Statementioning

confidence: 99%

Allosteric Signaling in PDZ Energetic Networks: Embedding Error Analysis

2023

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Allosteric signaling in proteins has been known for some half a century, yet how the signal traverses the protein remains an active area of research. Recently, the importance of electrostatics to achieve long-range signaling has become increasingly appreciated. Our laboratory has been working on developing network approaches to capture such interactions. In this study, we turn our attention to the well-studied allosteric model protein, PDZ. We study the allosteric dynamics on a perresidue basis in key constructs involving the PDZ domain, its allosteric effector, and its peptide ligand. We utilize molecular dynamics trajectories to create the networks for the constructs to explore the allosteric effect by plotting the heat kernel results onto axes defined by principal components. We introduce a new metric to quantitate the volume sampled by a residue in the latent space. We relate our findings to PDZ and the greater field of allostery.

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“…This then allows us to study the conformational interchange of substates using Markov state models derived from the trajectories obtained from MD simulations (MD-MSM). In our pipeline, MD-MSMs constitute a validated means to assess the extent to which an allosteric effector has restored the target activity. − We envision utilizing MD sector residues as allosteric points of control from which we will design small-molecule therapeutics. The efficacy of these potential drugs will be further explored with MD-MSMs.…”

Section: Introductionmentioning

confidence: 99%

Network Analysis of Molecular Dynamics Sectors in the p53 Protein

Fabry

Thayer

2022

ACS Omega

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Design of allosteric regulators is an emergent field in the area of drug discovery holding promise for currently untreated diseases. Allosteric regulators bind to a protein in one location and affect a distant site. The ubiquitous presence of allosteric effectors in biology and the success of serendipitously identified allosteric compounds point to the potential they hold. Although the mechanism of transmission of an allosteric signal is not unequivocally determined, one hypothesis suggests that groups of evolutionarily covarying residues within a protein, termed sectors, are conduits. A long-term goal of our lab is to allosterically modulate the activity of proteins by binding small molecules at points of allosteric control. However, methods to consistently identify such points remain unclear. Sector residues on the surfaces of proteins are a promising source of allosteric targets. Recently, we introduced molecular dynamics (MD)-based sectors; MD sectors capitalize on covariance of motion, in place of evolutionary covariance. By focusing on motional covariance, MD sectors tap into the framework of statistical mechanics afforded by the Boltzmann ensemble of structural conformations comprising the underlying data set. We hypothesized that the method of MD sectors can be used to identify a cohesive network of motionally covarying residues capable of transmitting an allosteric signal in a protein. While our initial qualitative results showed promise for the method to predict sectors, that a network of cohesively covarying residues had been produced remained an untested assumption. In this work, we apply network theory to rigorously analyze MD sectors, allowing us to quantitatively assess the biologically relevant property of network cohesiveness of sectors in the context of the tumor suppressor protein, p53. We revised the methodology for assessing and improving MD sectors. Specifically, we introduce a metric to calculate the cohesive properties of the network. Our new approach separates residues into two categories: sector residues and non-sector residues. The relatedness within each respective group is computed with a distance metric. Cohesive sector networks are identified as those that have high relatedness among the sector residues which exceeds the relatedness of the residues to the nonsector residues in terms of the correlation of motions. Our major finding was that the revised means of obtaining sectors was more efficacious than previous iterations, as evidenced by the greater cohesion of the networks. These results are discussed in the context of the development of allosteric regulators of p53 in particular and the expected applicability of the method to the drug design field in general.

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Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs

Cited by 4 publications

References 62 publications

Variable Regions of p53 Isoforms Allosterically Hard Code DNA Interaction

Variable Regions of p53 Isoforms Allosterically Hard Code DNA Interaction

Allosteric Signaling in PDZ Energetic Networks: Embedding Error Analysis

Network Analysis of Molecular Dynamics Sectors in the p53 Protein

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