About

Shabnam Akhtari is a professor at the Pennsylvania State University, based in the 339 McAllister Building. Her research interests include Number Theory, Geometry of Numbers, and Diophantine Analysis. Her work focuses on these areas, contributing to the understanding of their underlying mathematical structures and properties.

Research topics

• Chemistry
• Computer Science
• Photochemistry
• Computational chemistry
• Database
• Engineering
• Organic chemistry
• Software engineering
• Physics
• Systems engineering
• Biochemistry
• Atomic physics
• Computational science
• Stereochemistry
• Programming language

Selected publications

• Non-eigenstate Ab Initio Density Matrix Downfolding to produce Model Hamiltonians in Quantum Chemistry

  ChemRxiv · 2025-04-21

  preprintOpen accessSenior author

  Model Hamiltonians represent a convenient way of reducing complex problems of many-electron quantum mechanics to much simpler problems: they can fully reproduce the core behaviors of a system of interest by encoding only the dominant physical interactions and using only a small number of associated parameters. Model Hamiltonians have been successfully applied to describe many chemical and physical phenomena. Density Matrix Downfolding (DMD) [J. Chem. Phys. 2015, 143 (10), 102814] allows the derivation of model Hamiltonians, of any form, in a systematically improvable fashion, by matching the energy spectrum of ab initio Hamiltonians with those of the model Hamiltonians. This method allows not only the improvement of existing models but also the construction of accurate and efficient physical models for various systems. While DMD looks like a promising approach, it has rarely been applied within chemistry, and neither its limits nor practical performance are well understood. In this work we evaluated the performance of DMD, based on non-eigenstates of ab initio Hamiltonians, for several realistic chemical systems: benzene, naphthalene, FeSe, and a prototypical Fe(IV)=O complex found in the active sites of 2-oxoglutarate-dependent oxygenases. Our results show that DMD is a reliable and computationally efficient tool for obtaining optimized model Hamiltonians in quantum chemistry. This not only opens the door to studying complex systems at reduced computational cost but also to isolating and understanding the physical core principles that dominate their behavior — this might offer new insights for tuning, or even designing, chemical systems for applications ranging from biochemistry to catalysis.

  PublisherOA PDFDOI

• Experimental Evidence for Radical-Polar Crossover in Competition with, Rather Than Preceding, Alkene Formation by Microbial Ethylene-Forming Enzyme

  Journal of the American Chemical Society · 2025-11-18

  articleOpen access

  Ethylene-forming enzyme (EFE) catalyzes a reaction that sets it apart from other iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenases. In this reaction, all four oxidizing equivalents of O2 are unleashed upon 2OG, fragmenting it to ethylene (from C3 and C4) and three fully oxidized C1 equivalents (from C1, C2, and C5), while the would-be “prime substrate”, l-arginine, escapes unmodified. We previously proposed that ethylene formation proceeds by a radical-polar-crossover mechanism involving three unusual steps: (1) formal insertion of O2 between C1 and C2 of 2OG, forming a succinylperoxycarbonatoiron(II) complex and appending an additional oxygen to C1; (2) radical C–O coupling between a C3–C5-derived propionate-3-yl radical and a C1-derived Fe(III)-coordinated carbonate; and (3) polar fragmentation of the resultant (2-carboxyethyl)carbonatoiron(II) complex to ethylene, CO2, and carbonate. Here, we used isotopic labeling to distinguish the three C1 products and stopped-flow infrared (FTIR) spectroscopy to track their formation. The results confirm the prediction that C1 is not directly converted to CO2, implying that it must indeed become (bi)carbonate. Comparable kinetic data on the A198L variant, which produces ethylene and the abortive product, 3-hydroxypropionate, in similar quantities, reveal that these two products do not, as we had originally proposed, form in competing reactions of a common (2-carboxyethyl)carbonatoiron(II) intermediate. Rather, as suggested by a pair of computational studies separately led by Sayfutyarova and Christov, ethylene is formed in competition with radical coupling by an olefin-forming fragmentation that reduces the Fe(III) cofactor. In other words, crossover to the polar manifold thwarts rather than enables ethylene formation.

  PublisherOA PDFDOI

• Diverging Reaction Pathways and Key Intermediates in Ethylene Forming Enzyme

  The Journal of Physical Chemistry B · 2025-04-24 · 6 citations

  articleSenior authorCorresponding

  Ethylene-forming enzyme (EFE) is a non-heme iron(II)- and 2-oxoglutarate-(Fe(II)/2OG)-dependent oxygenase with distinct catalytic reactivity. While most Fe(II)/2OG-dependent oxygenases catalyze substrate hydroxylation with the 2OG decarboxylation to succinate, EFE primarily converts 2OG into CO2 and ethylene. In this work, we employ a multifaceted approach, including molecular dynamics, quantum mechanics and molecular mechanics methods, theoretical Mössbauer spectroscopy, and the analysis of the intrinsic electric field exerted by the protein environment, to examine possible reaction pathways. Our study reveals a novel second branch point, where the ethylene formation (EF) and 3-hydroxypropionate formation pathways diverge following the Fe(III)-carbonate and C3–C5-derived propion-3-yl radical intermediates, occurring earlier than suggested in previous studies. We identified multiple subsequent EF pathways characterized by a low-energy barrier and the formation of either Fe(II)-carbonates or Fe(II)-pyrocarbonates. Based on these findings, we introduce a revised reaction mechanism for ethylene formation in EFE, which is consistent with available experimental data and highlights the importance of retaining C2-derived CO2, generated in earlier stages, within the active site for the EF pathway. We also identified intermediates that can produce the Mössbauer quadrupole doublet peak observed in recent experiments and associated with unidentified Fe(II)-containing species characteristic to the ethylene-forming reaction pathway. This work provides new insights into both the first and second branchpoints of the ethylene-forming pathway that can be useful in EFE modifications aimed at shifting the product yield in the EF reaction.

  PublisherDOI

• Diverging Reaction Pathways and Key Intermediates in Ethylene Forming Enzyme

  ChemRxiv · 2025-01-15

  preprintOpen accessSenior author

  Ethylene-forming enzyme (EFE) is a non-heme iron (II)- and 2-oxoglutarate-(Fe(II)/2OG)-dependent oxygenase that exhibits distinct catalytic activity. While most Fe(II)/2OG-dependent oxygenases catalyze the substrate hydroxylation accompanied by the decarboxylation of the 2OG cosubstrate to succinate, EFE primarily converts the 2OG into CO2 and ethylene. Experimental studies suggest that the reaction mechanism of EFE does not involve the Fe(IV)=O (ferryl) intermediate central in the consensus mechanism for hydroxylation in Fe(II)/2OG-dependent oxygenases, and the ethylene-forming reaction pathway diverges early in the catalytic cycle after binding molecular oxygen. In this paper, we employ a multifaceted approach, including molecular dynamics, quantum mechanics and molecular mechanics methods, theoretical Mössbauer spectroscopy, and the analysis of the intrinsic electric field exerted by the protein environment, to examine possible reaction pathways for ethylene formation and hydroxylation in EFE. Our study reveals a new reaction pathway with a low energy barrier via the formation of Fe(II)-pyrocarbonates, which is different from all previously proposed reaction mechanisms. Based on our results, we introduce a revised reaction mechanism for the ethylene formation in the EFE that is consistent with the available experimental data. This work also provides new insights into both the first and second branchpoints of the ethylene-forming pathway that can be useful in EFE modifications aimed at shifting the product yield in the EF reaction.

  PublisherOA PDFDOI

• The Role of Intrinsic Electric Fields and 2-His-1-Carboxylate/Chloride Facial Triads in Modulating Reactivity of the 2-Oxoglutarate Dependent Enzymes

  ChemRxiv · 2025-06-23

  preprintOpen accessSenior author

  Iron (II)- and 2-oxoglutarate-dependent (Fe(II)/2OG) oxygenases form a large family of non-heme enzymes containing the Fe(II) center coordinated by two histidine residues and either a carboxylate or halide ligand, with 2OG acting as a co-substrate. Although these enzymes share a conserved 2-His-1-carboxylate/halide motif in their active sites, they catalyze a wide variety of oxidative chemical reactions. We here investigate two factors that can significantly impact the divergence in their observed catalytic functions, namely, the intrinsic electric field (IEF) exerted on the active site by the surrounding protein environment, and variations of the composition of the facial triad. Concretely, we first evaluate the IEFs in Fe(II)/2OG oxygenases and investigate whether the direction and magnitude of these computed IEFs correlate with catalytic function across multiple subfamilies of Fe(II)/2OG oxygenases. We also examine how these IEFs can influence the geometric and electronic structures of Fe(III)-superoxo intermediates formed in the active site of Fe(II)/2OG oxygenases upon binding O2, the initial step of their oxidative catalytic cycles. Additionally, we evaluated the role of the identity and orientation of the third ligand (Glu, Asp, or Cl) in the 2-His-1-carboxylate/halide facial triad in modulating the reactivity of the active site complexes. Our findings suggest that specific steps in the catalytic cycle are determined by the interplay between the IEF due to the protein environment and the structural features of the facial triad. The results of this study provide insights into the role of IEFs and the facial triads in the observed divergency of reactivity of Fe(II)/2OG enzymes.

  PublisherOA PDFDOI

• Noneigenstate <i>Ab Initio</i> Density Matrix Downfolding for Constructing Model Hamiltonians in Quantum Chemistry

  Journal of Chemical Theory and Computation · 2025-08-28

  articleSenior authorCorresponding

  Model Hamiltonians represent a convenient way of reducing complex problems of many-electron quantum mechanics to much simpler problems: they can fully reproduce the core behaviors of a system of interest by encoding only the dominant physical interactions and using only a small number of associated parameters. Model Hamiltonians have been successfully applied to describe many chemical and physical phenomena. Density matrix downfolding (DMD) [ J. Chem. Phys. 2015, 143 (10), 102814] allows the derivation of model Hamiltonians of any form in a systematically improvable fashion by matching the energy spectrum of ab initio Hamiltonians with those of the model Hamiltonians. This method allows not only the improvement of existing models but also the construction of accurate and efficient physical models for various systems. While DMD looks like a promising approach, it has rarely been applied within chemistry, and neither its limits nor its practical performance is well-understood. In this work, we evaluated the performance of DMD, based on noneigenstates of ab initio Hamiltonians, for several realistic chemical systems: benzene, naphthalene, FeSe, and a prototypical Fe(IV)═O complex found in the active sites of 2-oxoglutarate-dependent oxygenases. Our results show that DMD is a reliable and computationally efficient tool for obtaining optimized model Hamiltonians in quantum chemistry. This not only opens the door to studying complex systems at reduced computational cost but also to isolating and understanding the physical core principles that dominate their behavior─this might offer new insights for tuning or even designing chemical systems for applications ranging from biochemistry to catalysis.

  PublisherDOI

• Influence of Intrinsic Electric Fields and 2-His-1-Carboxylate/Chloride Facial Triad on the Active Sites of 2-Oxoglutarate–Dependent Enzymes

  ChemRxiv · 2025-11-09

  preprintOpen accessSenior author

  Iron (II)- and 2-oxoglutarate-dependent (Fe(II)/2OG) oxygenases form a large family of non-heme enzymes containing the Fe(II) center coordinated by two histidine residues and either a carboxylate or halide ligand, with 2OG acting as a co-substrate. Although these enzymes share a conserved 2-His-1-carboxylate/halide motif in their active sites, they catalyze a wide variety of oxidative chemical reactions. We here investigate two factors that can significantly impact the divergence in their observed catalytic functions, namely, the intrinsic electric field (IEF) exerted on the active site by the surrounding protein environment, and variations of the composition of the facial triad. Concretely, we first evaluate the IEFs in Fe(II)/2OG oxygenases and investigate whether the direction and magnitude of these computed IEFs correlate with catalytic function across multiple subfamilies of Fe(II)/2OG oxygenases. We also examine how these IEFs can influence the geometric and electronic structures of Fe(III)-superoxo intermediates formed in the active site of Fe(II)/2OG oxygenases upon binding O2, the initial step of their oxidative catalytic cycles. Additionally, we evaluated how the identity and orientation of the third ligand (Glu, Asp, or Cl) in the 2-His-1-carboxylate/halide facial triad influence the active site complexes. Our findings suggest that specific steps in the catalytic cycle are determined by the interplay between the IEF due to the protein environment and the structural features of the facial triad. The results of this study provide insights into the role of IEFs and the facial triads in the observed reaction specificity of different Fe(II)/2OG enzymes.

  PublisherDOI

• Influence of Intrinsic Electric Fields and 2-His-1-Carboxylate/Chloride Facial Triad on the Active Sites of 2-Oxoglutarate–Dependent Enzymes

  The Journal of Physical Chemistry B · 2025-11-25

  articleSenior authorCorresponding

  Iron(II)- and 2-oxoglutarate-dependent (Fe(II)/2OG) oxygenases form a large family of nonheme enzymes containing the Fe(II) center coordinated by two histidine residues and either a carboxylate or halide ligand, with 2OG acting as a cosubstrate. Although these enzymes share a conserved 2-His-1-carboxylate/halide motif in their active sites, they catalyze a wide variety of oxidative chemical reactions. We here investigate two factors that can significantly impact the divergence in their observed catalytic functions, namely, the intrinsic electric field (IEF) exerted on the active site by the surrounding protein environment, and variations of the composition of the facial triad. Concretely, we first evaluate the IEFs in Fe(II)/2OG oxygenases and investigate whether the direction and magnitude of these computed IEFs correlate with catalytic function across multiple subfamilies of Fe(II)/2OG oxygenases. We also examine how these IEFs can influence the geometric and electronic structures of Fe(III)-superoxo intermediates formed in the active site of Fe(II)/2OG oxygenases upon binding O2, the initial step of their oxidative catalytic cycles. Additionally, we evaluated how the identity and orientation of the third ligand (Glu, Asp, or Cl) in the 2-His-1-carboxylate/halide facial triad influence the active site complexes. Our findings suggest that specific steps in the catalytic cycle are determined by the interplay between the IEF due to the protein environment and the structural features of the facial triad. The results of this study provide insights into the role of IEFs and the facial triads in the observed reaction specificity of different Fe(II)/2OG enzymes.

  PublisherDOI

• Experimental and Computational Analysis of the Inability of an Iron(II)- and 2-Oxoglutarate-Dependent Aliphatic Halogenase to Mediate Fluorination

  ChemRxiv · 2025-11-19 · 1 citations

  articleOpen access

  Incorporation of fluorine into pharmaceuticals, agrochemicals, and molecular-imaging agents is of growing importance. Multiple synthetic fluorination methods have recently emerged, and metalloenzymes that are potentially capable of even C(sp3)–H fluorination have been reported. Nevertheless, direct, regioselective fluorination of aliphatic carbon centers remains an unsolved problem. Here, we show for the iron(II) and 2-oxoglutarate-dependent (Fe/2OG) L-Lysine 4-chlorinase, BesD, which can be envisaged to support C(sp3)–H fluorination by the direct cognate of its native chlorination mechanism, that the enzyme can (1) coordinate F– at its Fe(II) cofactor, (2) activate O2 to form a cis-FeIV(O)(F) (fluoroferryl) intermediate, and (3) use the intermediate to abstract hydrogen from its substrate. In what would be the key final step, fluorine (F•) transfer to the substrate radical is unable to compete with the hydroxyl-radical (HO•) "rebound" step characteristic of related hydroxylases. Electron paramagnetic resonance (EPR) and X-ray absorption spectroscopic data establish that fluorine remains bonded to the cofactor through steps 1-3 and therefore available for transfer to the substrate radical. QM/MM calculations suggest that the F•-coupling step is associated with an activation barrier considerably higher than that of HO• rebound, consistent with the observed outcome. The findings experimentally verify prior proposals that the impediment to C(sp3)–H fluorination by the canonical mechanism of an Fe/2OG halogenase lies in the final radical-coupling step and set the stage for exploration of whether a potentially surmountable geometric barrier or an insurmountable electronic one is primarily responsible.

  PublisherDOI

• Shapeshifting Ligands Mask Lewis Acidity of Dicationic Palladium(II)

  ChemRxiv · 2024-05-20 · 1 citations

  preprintOpen access

  Supporting ligands limit the degree of electrophilic ac-tivation for any substrate because they also reduce the Lewis acidity of the transition metal ion. Here, we tem-porarily mask the Lewis acidity of dicationic Pd(II) by using “shapeshifting” bidentate pyrimidine/olefin lig-ands L1 and L2. These ligands delocalize/relocalize charge via reversible C–N bond formation. So, although ligated dicationic Pd compounds [1]2+ and [2]2+ appear charge separated (distributed across Pd and ligand), they react comparably to a solvated Pd(II) dication. We also observe properties that are atypical of electrophilic cata-lysts (e.g. broader functional group tolerance). We pro-pose these properties originate from the more nucleo-philic (charge separated) state. More broadly, catalysts featuring reversible dynamics may be advantaged rela-tive to structurally static counterparts.

  PublisherOA PDFDOI

Frequent coauthors

• Sharon Hammes‐Schiffer

  Yale University

  12 shared

• Garnet Kin‐Lic Chan

  12 shared

• Nick S. Blunt

  7 shared

• Sheng Guo

  Institute of Plant Protection

  6 shared

• Qiming Sun

  Kunming University of Science and Technology

  6 shared

• Timothy C. Berkelbach

  6 shared

• Junzi Liu

  Johns Hopkins University

  6 shared

• James McClain

  6 shared

Education

• PhD, Chemistry

  Princeton University

  2017

• M.Sc., Chemistry

  Moskovskij gosudarstvennyj universitet imeni M V Lomonosova

  2011

Awards & honors

• ACS Physical Chemistry Division Young Investigator Award
• The Wiley Computers in Chemistry Outstanding Postdoc Award
• The Chemical Computing Group Excellence Award
• Princeton Centennial Fellowship
• Vladimir Potanin Foundation Fellowship