Chu Zheng

All Publications

• Enhanced active-site electric field accelerates enzyme catalysis. Nature chemistry Zheng, C., Ji, Z., Mathews, I. I., Boxer, S. G. 2023

  Abstract

  The design and improvement of enzymes based on physical principles remain challenging. Here we demonstrate that the principle of electrostatic catalysis can be leveraged to substantially improve a natural enzyme's activity. We enhanced the active-site electric field in horse liver alcohol dehydrogenase by replacing the serine hydrogen-bond donor with threonine and replacing the catalytic Zn2+ with Co2+. Based on the electric field enhancement, we make a quantitative prediction of rate acceleration-50-fold faster than the wild-type enzyme-which was in close agreement with experimental measurements. The effects of the hydrogen bonding and metal coordination, two distinct chemical forces, are described by a unified physical quantity-electric field, which is quantitative, and shown here to be additive and predictive. These results suggest a new design paradigm for both biological and non-biological catalysts.

  View details for DOI 10.1038/s41557-023-01287-x

  View details for PubMedID 37563323

• A two-directional vibrational probe reveals different electric field orientations in solution and an enzyme active site. Nature chemistry Zheng, C., Mao, Y., Kozuch, J., Atsango, A. O., Ji, Z., Markland, T. E., Boxer, S. G. 2022

  Abstract

  The catalytic power of an electric field depends on its magnitude and orientation with respect to the reactive chemical species. Understanding and designing new catalysts for electrostatic catalysis thus requires methods to measure the electric field orientation and magnitude at the molecular scale. We demonstrate that electric field orientations can be extracted using a two-directional vibrational probe by exploiting the vibrational Stark effect of both the C=O and C-D stretches of a deuterated aldehyde. Combining spectroscopy with molecular dynamics and electronic structure partitioning methods, we demonstrate that, despite distinct polarities, solvents act similarly in their preference for electrostatically stabilizing large bond dipoles at the expense of destabilizing small ones. In contrast, we find that for an active-site aldehyde inhibitor of liver alcohol dehydrogenase, the electric field orientation deviates markedly from that found in solvents, which provides direct evidence for the fundamental difference between the electrostatic environment of solvents and that of a preorganized enzyme active site.

  View details for DOI 10.1038/s41557-022-00937-w

  View details for PubMedID 35513508

• A unifying electrostatic basis for designing enzymes faster than natural ones Zheng, C., Ji, Z., Mathews, I. I., Boxer, S. G. CELL PRESS. 2023: 483A

  View details for Web of Science ID 000989629702595

• Carbon-deuterium bonds as reporters of electric fields in solvent and protein environments. Biophysical journal Fried, S. D., Kirsh, J. M., Zheng, C., Mao, Y., Markland, T. E., Boxer, S. G. 2023; 122 (3S1): 481a

  View details for DOI 10.1016/j.bpj.2022.11.2574

  View details for PubMedID 36784478

• A unifying electrostatic basis for designing enzymes faster than natural ones. Biophysical journal Zheng, C., Ji, Z., Mathews, I. I., Boxer, S. G. 2023; 122 (3S1): 483a

  View details for DOI 10.1016/j.bpj.2022.11.2583

  View details for PubMedID 36784486

• Carbon-deuterium bonds as reporters of electric fields in solvent and protein environments Fried, S. E., Kirsh, J. M., Zheng, C., Mao, Y., Markland, T. E., Boxer, S. G. CELL PRESS. 2023: 481A

  View details for Web of Science ID 000989629702586

• Solvent Organization and Electrostatics Tuned by Solute Electronic Structure: Amide versus Non-Amide Carbonyls. The journal of physical chemistry. B Fried, S. D., Zheng, C., Mao, Y., Markland, T. E., Boxer, S. G. 2022

  Abstract

  The ability to exploit carbonyl groups to measure electric fields in enzymes and other complex reactive environments by using the vibrational Stark effect has inspired growing interest in how these fields can be measured, tuned, and ultimately designed. Previous studies have concentrated on the role of the solvent in tuning the fields exerted on the solute. Here, we explore instead the role of the solute electronic structure in modifying the local solvent organization and electric field exerted on the solute. By measuring the infrared absorption spectra of amide-containing molecules, as prototypical peptides, and contrasting them with non-amide carbonyls in a wide range of solvents, we show that these solutes experience notable differences in their frequency shifts in polar solvents. Using vibrational Stark spectroscopy and molecular dynamics simulations, we demonstrate that while some of these differences can be rationalized by using the distinct intrinsic Stark tuning rates of the solutes, the larger frequency shifts for amides and dimethylurea primarily result from the larger solvent electric fields experienced by their carbonyl groups. These larger fields arise due to their stronger p-π conjugation, which results in larger C═O bond dipole moments that further induce substantial solvent organization. Using electronic structure calculations, we decompose the electric fields into contributions from solvent molecules that are in the first solvation shell and those from the bulk and show that both of these contributions are significant and become larger with enhanced conjugation in solutes. These results show that structural modifications of a solute can be used to tune both the solvent organization and electrostatic environment, indicating the importance of a solute-centric paradigm in modulating and designing the electrostatic environment in condensed-phase chemical processes.

  View details for DOI 10.1021/acs.jpcb.2c03095

  View details for PubMedID 35901512

• Tuning solvent electrostatic environment of amide carbonyls as prototypical peptide backbones Fried, S. E., Zheng, C., Mao, Y., Markland, T. E., Boxer, S. G. CELL PRESS. 2022: 186A

  View details for Web of Science ID 000759523001175

• A two-directional vibrational probe reveals the distinct electric field orientation at the active site of liver alcohol dehydrogenase Zheng, C., Mao, Y., Kozuch, J. A., Atsango, A. O., Ji, Z., Markland, T. E., Boxer, S. G. CELL PRESS. 2022: 441A

  View details for Web of Science ID 000759523002685

• Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case. The journal of physical chemistry. B Kozuch, J., Schneider, S. H., Zheng, C., Ji, Z., Bradshaw, R. T., Boxer, S. G. 2021

  Abstract

  Noncovalent interactions underlie nearly all molecular processes in the condensed phase from solvation to catalysis. Their quantification within a physically consistent framework remains challenging. Experimental vibrational Stark effect (VSE)-based solvatochromism can be combined with molecular dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid molecules and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach toward more complex (bio)molecules, such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based electric fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the electric fields are correlated to conformation-dependent effects of the flexible PenG side chain, including both the local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in three-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for experiment-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)molecules.

  View details for DOI 10.1021/acs.jpcb.1c00578

  View details for PubMedID 33900769

• Bimetallic cooperative effect on O-O bond formation: copper polypyridyl complexes as water oxidation catalyst DALTON TRANSACTIONS Su, X., Zheng, C., Hu, Q., Du, H., Liao, R., Zhang, M. 2018; 47 (26): 8670–75

  Abstract

  The performance of water oxidation catalysis by a Cu-based polypyridyl complex, [CuII(TPA)(OH2)]2+ (1H; TPA = tris-(pyridylmethyl)amine), has been investigated in neutral aqueous solution by electrochemical methods. Compared with our previously reported binuclear catalyst, [(BPMAN)(CuII)2(μ-OH)]3+ (2; BPMAN = 2,7-[bis(2-pyridylmethyl)aminomethyl]-1,8-naphthyridine), mononuclear catalyst 1 has a higher overpotential and lower catalytic activity toward water oxidation under the same conditions. Experimental results revealed that the O-O bond formation occurred via a water nucleophilic attack mechanism in which formal CuIV(O) is proposed as a key intermediate for the mononuclear catalyst 1H. In contrast, for the binuclear catalyst, O-O bond formation was facilitated by bimetallic cooperation between the two CuIII centers.

  View details for DOI 10.1039/c8dt01675e

  View details for Web of Science ID 000437317700021

  View details for PubMedID 29897064