More Like this

1. The Energetics and Evolution of Oxidoreductases in Deep Time

   https://doi.org/10.1002/prot.26563  

   McGuinness, Kenneth N.; Fehon, Nolan; Feehan, Ryan; Miller, Michelle; Mutter, Andrew C.; Rybak, Laryssa A.; Nam, Justin; AbuSalim, Jenna E.; Atkinson, Joshua T.; Heidari, Hirbod; et al (January 2024, Proteins: Structure, Function, and Bioinformatics)

   Dokholyan, Nikolay (Ed.)

   Abstract The core metabolic reactions of life drive electrons through a class of redox protein enzymes, the oxidoreductases. The energetics of electron flow is determined by the redox potentials of organic and inorganic cofactors as tuned by the protein environment. Understanding how protein structure affects oxidation–reduction energetics is crucial for studying metabolism, creating bioelectronic systems, and tracing the history of biological energy utilization on Earth. We constructed ProtReDox (https://protein-redox-potential.web.app), a manually curated database of experimentally determined redox potentials. With over 500 measurements, we can begin to identify how proteins modulate oxidation–reduction energetics across the tree of life. By mapping redox potentials onto networks of oxidoreductase fold evolution, we can infer the evolution of electron transfer energetics over deep time. ProtReDox is designed to include user‐contributed submissions with the intention of making it a valuable resource for researchers in this field. 

   more » « less
2. A Binuclear Cu _A Center Designed in an All α-Helical Protein Scaffold

   https://doi.org/10.1021/jacs.0c04226  

   Mirts, Evan N.; Dikanov, Sergei A.; Jose, Anex; Solomon, Edward I.; Lu, Yi (July 2020, Journal of the American Chemical Society)

   The primary and secondary coordination spheres of metal binding sites in metalloproteins have been investigated extensively, leading to the creation of high-performing functional metalloproteins; however, the impact of the overall structure of the protein scaffold on the unique properties of metalloproteins has rarely been studied. A primary example is the binuclear CuA center, an electron transfer cupredoxin domain of photosynthetic and respiratory complexes and, recently, a protein co-regulated with particulate methane and ammonia monooxygenases. The redox potential, Cu–Cu spectroscopic features, and a valence delocalized state of CuA are difficult to reproduce in synthetic models, and every artificial protein CuA center to-date has used a modified cupredoxin. Here we present a fully functional CuA center designed in a structurally non-homologous protein, cytochrome c peroxidase (CcP), by only two mutations (CuACcP). We demonstrate with UV-visible absorption, resonance Raman, and MCD spectroscopy that CuACcP is valence delocalized. CW and pulsed (HYSCORE) X-band EPR show it has a highly compact gz area and small Az hyperfine principal value with g and A tensors that resemble axially perturbed CuA. Stopped-flow kinetics found that CuA formation proceeds through a single T2Cu intermediate. The reduction potential of CuACcP is comparable to native CuA and can transfer electrons to a physiological redox partner. We built a structural model of the designed Cu binding site from EXAFS and validated it by mutation of coordinating Cys and His residues, revealing that a triad of residues (R48C, W51C, and His52) rigidly arranged on one α-helix is responsible for chelating the first Cu atom and that His175 stabilizes the binuclear complex by rearrangement of the CcP heme-coordinating helix. This design is a demonstration that a highly conserved protein fold is not uniquely necessary to induce certain characteristic physical and chemical properties to a metal redox center. 

   more » « less
3. Exploring the folding energy landscapes of heme proteins using a hybrid AWSEM-heme model

   https://doi.org/10.1007/s10867-021-09596-3  

   Chen, Xun; Lu, Wei; Tsai, Min-Yeh; Jin, Shikai; Wolynes, Peter G. (March 2022, Journal of Biological Physics)

   Abstract Heme is an active center in many proteins. Here we explore computationally the role of heme in protein folding and protein structure. We model heme proteins using a hybrid model employing the AWSEM Hamiltonian, a coarse-grained forcefield for the protein chain along with AMBER, an all-atom forcefield for the heme. We carefully designed transferable force fields that model the interactions between the protein and the heme. The types of protein–ligand interactions in the hybrid model include thioester covalent bonds, coordinated covalent bonds, hydrogen bonds, and electrostatics. We explore the influence of different types of hemes (heme b and heme c) on folding and structure prediction. Including both types of heme improves the quality of protein structure predictions. The free energy landscape shows that both types of heme can act as nucleation sites for protein folding and stabilize the protein folded state. In binding the heme, coordinated covalent bonds and thioester covalent bonds for heme c drive the heme toward the native pocket. The electrostatics also facilitates the search for the binding site. 

   more » « less
4. Controlling heme redox properties in peptide amphiphile fibers with sequence and heme loading ratio

   https://doi.org/10.1016/j.bpj.2024.05.021  

   Dutta, Chiranjit; Lopez, Virginia; Preston, Conner; Rudra, Nimesh; Chavez, Alex_Mauricio Valdivia; Rogers, Abigail M; Solomon, Lee A (July 2024, Biophysical Journal)

   Koder, Ronald (Ed.)

   Controlling the reduction midpoint potential of heme B is a key factor in many bioelectrochemical reactions, including long-range electron transport. Currently, there are a number of globular model protein systems to study this biophysical parameter; however, there are none for large polymeric protein model systems (e.g., the OmcS protein from G. sulfurreducens). Peptide amphiphiles, short peptides with a lipid tail that polymerize into fibrous structures, fill this gap. Here, we show a peptide amphiphile model system where one can tune the electrochemical potential of heme B by changing the loading ratio and peptide sequence. Changing the loading ratio resulted in the most significant increase, with values as high as −22 mV down to −224 mV. Circular dichroism spectra of certain sequences show Cotton effects at lower loading ratios that disappear as more heme B is added, indicating an ordered environment that becomes disrupted if heme B is overpacked. These findings can contribute to the design of functional self-assembling biomaterials. 

   more » « less
5. Computational design of quinone electrolytes for redox flow batteries using high-throughput machine learning and theoretical calculations

   https://doi.org/10.3389/fceng.2022.1086412  

   Wang, Fei; Li, Jipeng; Liu, Zheng; Qiu, Tong; Wu, Jianzhong; Lu, Diannan (January 2023, Frontiers in Chemical Engineering)

   Jesus Flores Cerrillo, Praxair (Ed.)

   Molecular design of redox-active materials with higher solubility and greater redox potential windows is instrumental in enhancing the performance of redox flow batteries Here we propose a computational procedure for a systematic evaluation of organic redox-active species by combining machine learning, quantum-mechanical, and classical density functional theory calculations. 1,517 small quinone molecules were generated from the building blocks of benzoquinone, naphthoquinone, and anthraquinone with different substituent groups. The physics-based methods were used to predict HOMO-LUMO gaps and solvation free energies that account for the redox potential differences and aqueous solubility, respectively. The high-throughput calculations were augmented with the quantitative structure-property relationship analyses and machine learning/graph network modeling to evaluate the materials’ overall behavior. The computational procedure was able to reproduce high-performance cathode electrolyte materials consistent with experimental observations and identify new electrolytes for RFBs by screening 100,000 di-substituted quinone molecules, the largest library of redox-active quinone molecules ever investigated. The efficient computational platform may facilitate a better understanding of the structure-function relationship of quinone molecules and advance the design and application of all-organic active materials for RFBs. 

   more » « less