Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates

Dixit, Vaibhav A.; Blumberger, Jochen; Vyas, Shivam Kumar

doi:10.1016/j.bpj.2021.07.007

Cited by 3 publications

(10 citation statements)

References 77 publications

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“…The F393A mutation lowers the cofactor distance but increases the ET Δ G °. The total ET λ was decomposed into the respective protein and solvent contributions (λ prot , λ solv ) using a procedure reported in the Methods section and earlier . The conservative nature of the Phe to Trp substitution leads to very similar λ prot and λ solv values.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Explicit MD simulations on both redox states were run in triplicate (starting from the equilibrated protein structure) for each ligand-free (LF) and ligand-bound (LB) BM3 followed by the estimation of vertical energy gaps (Δ E ). , Top three docked poses were considered for running 20 ns MD simulations and ET parameter calculations. Thus, a total of 360 ns long simulations were run for each substrate-bound complex.…”

Section: Methodsmentioning

confidence: 99%

“…where H ab is the electronic coupling matrix between the cofactor estimated from distance dependence reported earlier, 27,31 k B is the Boltzmann constant, T temperature in Kelvin, and ℏ is the reduced Planck's constant. Protein Preparation.…”

Section: Ro (A)mentioning

confidence: 99%

“…In recent years, the empirical or semi-empirical Marcus theory coupled with MD simulations has been utilized for a reasonably accurate estimation of ET rates in multi-Heme bacterial cytochromes − and hemoglobin . Details of the underlying theory and approach are given in the Methods section.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3

et al. 2022

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Bacterial cytochromes P450 BM3 (CYP450 BM3) catalyze reactions of industrial importance. Despite many successful biotransformations, robust (re)design for novel applications remains challenging. Rational design and evolutionary approaches are not always successful, highlighting a lack of complete understanding of the mechanisms of electron transfer (ET) modulations. Thus, the full potential of CYP450 reactions remains under-exploited. In this work, we report the first molecular dynamics (MD)-based explicit prediction of BM3 ET parameters (reorganization energies; λ and ET free energies; ΔG°), and log ET rates (log k ET) using the Marcus theory. Overall, the calculated ET rates for the BM3 wild-type (WT), mutants (F393 and L86), ligand-bound state, and ion concentrations agree well with experimental data. In ligand-free (LF) BM3, mutations modulate k ET via ET ΔG°. Simulations show that the experimental ET rate enhancement is due to increased driving force (more negative ΔG°) upon ligation. This increase is related to the protein reorganization required to accommodate the ligand in the binding pocket rather than binding interactions with the ligand. Our methodology (CYPWare 1.0) automates all the stages of the MD simulation step-up, energy calculations, and estimation of ET parameters. CYPWare 1.0 and this work thus represent an important advancement in the CYP450 ET rate predictions, which has the potential to guide the redesign of ET enzymes. This program and a Web tool are available on GitHub for academic research.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Ro (A)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3

et al. 2022

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“…The reversible oxygen binding of Hb to oxygen depends on the reduced state of iron atoms in the structure of Hb. However, one or more iron ions in methemoglobin are in the oxidized state and are unable to bind oxygen while increasing the affinity of Hb for oxygen and shifting the oxygen dissociation curve to the left, resulting in decreasing its ability to release and deliver oxygen ( Dixit et al, 2021 ). However, elevated methemoglobin in the recipient has rarely been reported when HBOCs are applied to preserve grafts.…”

Section: Overview Of Hbocsmentioning

confidence: 99%

Hemoglobin-Based Oxygen Carriers: Potential Applications in Solid Organ Preservation

Cao

Wang

et al. 2021

Front. Pharmacol.

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Ameliorating graft injury induced by ischemia and hypoxia, expanding the donor pool, and improving graft quality and recipient prognosis are still goals pursued by the transplant community. The preservation of organs during this process from donor to recipient is critical to the prognosis of both the graft and the recipient. At present, static cold storage, which is most widely used in clinical practice, not only reduces cell metabolism and oxygen demand through low temperature but also prevents cell edema and resists apoptosis through the application of traditional preservation solutions, but these do not improve hypoxia and increase oxygenation of the donor organ. In recent years, improving the ischemia and hypoxia of grafts during preservation and repairing the quality of marginal donor organs have been of great concern. Hemoglobin-based oxygen carriers (HBOCs) are “made of” natural hemoglobins that were originally developed as blood substitutes but have been extended to a variety of hypoxic clinical situations due to their ability to release oxygen. Compared with traditional preservation protocols, the addition of HBOCs to traditional preservation protocols provides more oxygen to organs to meet their energy metabolic needs, prolong preservation time, reduce ischemia–reperfusion injury to grafts, improve graft quality, and even increase the number of transplantable donors. The focus of the present study was to review the potential applications of HBOCs in solid organ preservation and provide new approaches to understanding the mechanism of the promising strategies for organ preservation.

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Sulfotransferase‐mediated phase II drug metabolism prediction of substrates and sites using accessibility and reactivity‐based algorithms

Vyas,

Das,

Suryanarayana Murty

et al. 2024

Molecular Informatics

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Sulphotransferases (SULTs) are a major phase II metabolic enzyme class contributing ~20 % to the Phase II metabolism of FDA‐approved drugs. Ignoring the potential for SULT‐mediated metabolism leaves a strong potential for drug‐drug interactions, often causing late‐stage drug discovery failures or black‐boxed warnings on FDA labels. The existing models use only accessibility descriptors and machine learning (ML) methods for class and site of sulfonation (SOS) predictions for SULT. In this study, a variety of accessibility, reactivity, and hybrid models and algorithms have been developed to make accurate substrate and SOS predictions. Unlike the literature models, reactivity parameters for the aliphatic or aromatic hydroxyl groups (R/Ar−O−H), the Bond Dissociation Energy (BDE) gave accurate models with a True Positive Rate (TPR)=0.84 for SOS predictions. We offer mechanistic insights to explain these novel findings that are not recognized in the literature. The accessibility parameters like the ratio of Chemgauss4 Score (CGS) and Molecular Weight (MW) CGS/MW and distance from cofactor (Dis) were essential for class predictions and showed TPR=0.72. Substrates consistently had lower BDE, Dis, and CGS/MW than non‐substrates. Hybrid models also performed acceptablely for SOS predictions. Using the best models, Algorithms gave an acceptable performance in class prediction: TPR=0.62, False Positive Rate (FPR)=0.24, Balanced accuracy (BA)=0.69, and SOS prediction: TPR=0.98, FPR=0.60, and BA=0.69. A rule‐based method was added to improve the predictive performance, which improved the algorithm TPR, FPR, and BA. Validation using an external dataset of drug‐like compounds gave class prediction: TPR=0.67, FPR=0.00, and SOS prediction: TPR=0.80 and FPR=0.44 for the best Algorithm. Comparisons with standard ML models also show that our algorithm shows higher predictive performance for classification on external datasets. Overall, these models and algorithms (SOS predictor) give accurate substrate class and site (SOS) predictions for SULT‐mediated Phase II metabolism and will be valuable to the drug discovery community in academia and industry. The SOS predictor is freely available for academic/non‐profit research via the GitHub link.

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Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates

Cited by 3 publications

References 77 publications

Mechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3

Mechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3

Hemoglobin-Based Oxygen Carriers: Potential Applications in Solid Organ Preservation

Sulfotransferase‐mediated phase II drug metabolism prediction of substrates and sites using accessibility and reactivity‐based algorithms

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