Yong Zhang

High Accuracy Computational Chemistry to Help Solve Experimental Problems Our research focuses on developing and utilizing computational methods to provide accurate information for molecular and biomolecular systems, particularly those of broad impact on biomedicine and sustainable chemistry. Our high accuracy computational results with errors typically within 1-3% experimental ranges build a strong basis to provide critical missing information to help understand important experimental data, correct experimental errors, and guide future experiments with better desired properties/functions, which have been supported by many new experiments. Our prior research has enabled 1) unprecedented mechanistic details for >100 reactions of important therapeutic agents, proteins of clinical interest, and green catalysts/biocatalysts. 2) accurate predictions of ~20 widely used spectroscopic properties with theory-versus-experiment correlation coefficient R² around 0.99; 3) structure refinement and determination for active sites of ~20 metalloproteins with accuracy like small molecules. Among a total of 147 published/accepted papers, 56 are in high-profile Q1 multidisciplinary chemistry journals. The average journal impact factor of all his papers published at US tenured/tenure-track positions is 8.5. The complete list of the publications is here: https://scholar.google.com/citations?user=hDumUHUAAAAJ&hl=en After receiving the training in this lab at Stevens, all PhD students won some awards such as Outstanding Achievement Award in the Doctoral Program in Chemistry and many undergraduate students won up to 7 awards and scholarships, including national level honors such as ACS Division of Physical Chemistry Undergraduate Award and ACS Division of Inorganic Chemistry Undergraduate Award. Many students have publications in prestigious or even top journals, including undergraduate students. Many students become scientists and professors in academia, industry (such as Estee Lauder, ExxonMobil, SandboxAQ from Google, TikTok, Enzo Life Sciences, ProBio, InVitro Cell Research), or federal government agency, after graduation from this lab. For those who went to graduate and medical schools, each receives up to 7 offers from prominent universities such as Yale, John Hopkins, Cornell/Rochefeller/MSK, UCLA, University of Michigan, New York University, Rutgers. Our current research interests are mainly in the following areas: 1) Computational mechanistic studies of bioengineered catalysts for sustainable chemistry and drug synthesis. One important topic to help make our earth sustainable is to develop inexpensive non-toxic catalysts to perform highly reactive and selective atom-economic chemical transformations for materials, drugs, and other useful substances, at room temperature and ambient pressure, in aqueous solution. Novel heme protein-based biocatalysts exhibit excellent catalytic performance for a wide range of non-native chemical reactions. A recent Nobel Prize was awarded to a few experimental pioneers in this field. Our group has provided some first and significant mechanistic insights into the electronic structures of heme carbenes and the origins of their reactivity, stereoselectivity, and chemoselectivity results in cyclopropanation, C-H insertion, N-H insertion, and Si-H insertion to help develop new chemistry for experimental synthesis work. Another area is to design bio-inspired catalysts and enzymes for transforming greenhouse gases such as CO₂ and N₂O into useful feedstock chemicals for sustainable chemical synthesis. 2) AI predictions of molecular/biomolecular properties and chemical/biochemical reactions. AI has been transforming the research field with two Nobel Prizes being recently awarded. However, AI tools in chemistry areas are mostly known for fast predictions but with significantly less accuracy than quantum chemistry predictions, especially for systems beyond normal organic molecules. Building on our previous strength in high accuracy predictions of experimental properties, we are developing new AI methods particularly deep learning approaches to improve the accuracy toward the quantum chemistry level while keeping its speedy feature. 3) Computational investigations of metalloprotein/metal mediated binding, formation, conversion, and detection of biological HNO and NO. These small molecules play vital roles in the cellular survival and signaling/regulation activities. Studies of NO's effects in biomedicine have been awarded Nobel Prize. Our group has been providing some previously unknown critical structural and mechanistic information in this area, such as the first atomic level HNO bound protein active site structure, first heme and non-heme protein mediated HNO to NO conversion mechanistic pathway details, and first metal-based selective HNO sensor's reactivity mechanism, and first non-native one-electron reduction reactivity mechanism for NO in models of nitric oxide reductases. We are investigating new designs of bio-inspired NO reduction agents. 4) Quantum chemical studies of accurate drug binding structures and pro-drug and covalent drug activation mechanisms. In the traditional structure-based drug discovery area of non-covalent binding drugs, there are difficulties in obtaining x-ray structures of many drug-biomolecule complexes and accuracy problems of conventional x-ray crystallography. Our group provided accurate structures of important bisphosphonate-protein complexes and their associate interaction modes to help find new drug leads and understand their drug activity and selectivity. Such drugs have a billion-dollar global pharmaceutical market and exhibit excellent activities in treating bone-resorption diseases, Paget's disease, and cancer. In the non-traditional drug development areas, our group revealed the activation mechanism of the bestseller anticancer prodrug cisplatin and studied prodrugs such as hydroxyurea for HNO. We are exploring covalent drugs with new mechanisms.

Journal Article 1. McCarthy, E.; Baizhigitova, D.; Chu, J. M.; Zhang, Y. (2025). Oxidative and Hydrolytic HNO Formation from a Clinical Drug Hydroxyurea Catalyzed by Horseradish Peroxidase: Basic Mechanism, Active Site Effect, and Implications for Drug Design. Jacs Au (6 ed., vol. 5, pp. 2849-2860). https://pubs.acs.org/doi/full/10.1021/jacsau.5c00438. 2. Couture, B. M.; Cui, R.; Chu, J. M.; Shen, Z.; Khare, S. D.; Zhang, Y.; Fasan, R. (2024). Radical-mediated regiodivergent C(sp³)–H functionalization of N-substituted indolines via enzymatic carbene transfer. Chem Catalysis (11 ed., vol. 4). 3. Roy, S.; Wang, Y.; Zhao, X.; Dayananda, T.; Chu, J. M.; Zhang, Y.; Fasan, R. (2024). Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles. Journal of the