Electrostatics in Biological Systems

29. Electrostatics of Covalent Inhibition During Antibiotic Resistance

The widespread design of covalent drugs has focused on crafting reactive groups of proper electrophilicity and positioning. We found that environmental electric fields projected onto a reactive chemical bond, an overlooked design element, play essential roles in the covalent inhibition of TEM-1 β-lactamase by avibactam. 

Zhi et al., J. Am. Chem. Soc., 2022
Protein Electric Fields Enable Faster and Longer-Lasting Covalent Inhibition of β-Lactamases.
DOI: 10.1021/jacs.2c09876

28. Quantifying Electrostatics at Model Membranes

We have used electrode-supported model membranes in many previous studies to control the transmembrane potential. Here we quantify the transmembrane electrostatics combining SEIRA spectroscopy and MD simulations.

Utesch et al., J. Phys. Chem. B, 2022
Potential Distribution across Model Membranes.
DOI: 10.1021/acs.jpcb.2c05372

27. 2D Vibrational Stark Probes

Vibrational Stark probes like C=O groups are inherently sensitive only to electric along the bond axis and thus one-dimensional probes. Here, we show that the deuterated aldhehyd gives a 2D view using the C=O and C-D modes.

Zheng & Mao et al., Nat. Chem., 2022
Electric field orientations in solution and enzyme active site revealed by a two-directional vibrational probe.
DOI: 10.1038/s41557-022-00937-w

26. Nitrile IR Intensities Calibrate Electric Fields

Nitriles are almost ideal electric field probes when utilizing the vibrational Stark effect frequency shift. Almost, because they suffer from the additional H-bonding shift. Here, we show that the IR Intensity does not suffer from such effect and is the true ideal electric field strength indicator.

Weaver et al., J. Am. Chem. Soc., 2022
Nitrile IR intensities characterize electric fields and hydrogen bonding in protic, aprotic and protein environments.
DOI: 10.1021/jacs.2c00675

24. Antibiotic Resistance trough Electrostatics and Chemical Positioning

What are the physical origins of antibiotic resistance? Using experiments and theory we explore the active site electric fields and chemical positioning in β-lactamases.

Schneider & Kozuch et al., ACS Centr. Sci., 2021
The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases.
DOI: 10.1021/acscentsci.1c00880

23. Electric Field Changes during Photoisomerization in Phytochromes

Photoisomerization in phytochromes leads to a functionally relevant transition of an α-helical segment to a β-sheet. Using nitrile probes on non-natural amino acids reveals electric field changes during this secondary structural change.

Kraskov et al., Biochemistry, 2021
Local Electric Field Changes during the Photoconversion of the Bathy Phytochrome Agp2.
DOI: 10.1021/acs.biochem.1c00426

22. Using the Vibrational Stark Effect to Test MD Force Fields

Molecular dynamics force fields rely on careful parameterization and experimental methods are required to assure their accuracy. The vibrational Stark effect quantifies local electrostatic interation and is very useful to test and refine force fields.

Kozuch et al., J. Phys. Chem. B, 2021
Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case.
DOI: 10.1021/acs.jpcb.1c00578

21. The CO Ligand in CO-inhibited Cytochrome c Oxidase is Destabilized Electrostatically Prior to Dissosiation

The CO molecule is a known inhibitor of the reduced heme a3 active site in cytochrom c oxidase. However, even prior to oxidative dissociation, the CO is electrostatically destabilized in its position as ligand.

Baserga et al., Front. Sci., 2021
Quantification of Local Electric Field Changes at the Active Site of Cytochrome c Oxidase by Fourier Transform Infrared Spectroelectrochemical Titrations.
DOI: 10.3389/fchem.2021.669452

20. Site-specific 13C-labeling of β-Lactam Drugs

In order to perform our study (24) on the evolution of electric fields in β-lactamases, we need site-specifically 13C-labeled penicillin G and cefotaxime. To our surprise there are no commercial sources, so we did it ourselves.

Kozuch et al., ACS Chem. Bio., 2020
Biosynthetic incorporation of site-specific isotopes in β-lactam antibiotics enables biophysical studies.
DOI: 10.1021/acschembio.9b01054

19. QCL-boosted Vibrational Stark Spectroscopy

In vibrational Stark spectroscopy (VSS) kV-voltages are applied between Ni-coated FTIR windows, leading to photon limitation. Using QCL-based spectrometers the sensitivity of VSS can be improved considerably.

Szczepaniak et al., Appl. Spec., 2019
Vibrational Stark Spectroscopy of Fluorobenzene Using Quantum Cascade Laser Dual Frequency Combs.
DOI: 10.1177/0003702819888503

16. How strong are the Interfacial Electric Fields sensed by a redox protein at an Electrode

We introduce the non-canonical amino acid cyano-phenylalanine into cytochrome c as a vibrational Stark probe. Using this probe determine the interfacial electric fields at various positions of the protein.

Biava et al., J. Phys. Chem. B, 2018
Long-range modulations of the electric fields in proteins.
DOI: 10.1021/acs.jpcb.8b03870

12. Monitoring how Transmembrane Electrostatics reorient a-helices in Membranes

Antimicrobial peptides are the first line of defense after contact of an infectious invader, often acting via interactions with the target membrane. The transmembrane electrostatics can play a major governing role in antimicrobial action. We show, for the first time using SEIRAS, that we can control the large-scale reorientation of AMP helices to form the active ion channel form.

Forbrig et al., Langmuir, 2018
Monitoring the orientational changes of alamethicin during incorporation in bilayer lipid membranes.
DOI: 10.1021/acs.langmuir.7b04265

11. Measuring Interfacial Electric Fields at Functionalized Electrodes

A comprehensive understanding of physical and chemical processes at biological membranes requires the knowledge of the interfacial electric field which is a key parameter for controlling molecular structures and reaction dynamics at electrodes. We utilize the vibrational Stark effect quantify interfacial electric fields.

Staffa et al., J. Phys. Chem. C, 2017
Determination of the local electric field at Au/SAM interfaces using the vibrational Stark effect.
DOI: 10.1021/acs.jpcc.7b08434

6. The mitochondrial human voltage-dependent anion channel (HVDAC) acts via deformation Its b-barrel structure

The voltage-dependent anion channel (VDAC) regulates the transfer of metabolites between the cytosol and the mitochondrium. Opening and partial closing of the channel is known to be driven by the transmembrane potentia. Our results indicate alterations of the inclination angle of the β-strands as crucial molecular events, reflecting an expansion or contraction of the β-barrel pore.

Kozuch et al., Phys. Chem. Chem. Phys., 2014
Voltage-dependent structural changes of the membrane-bound anion channel hVDAC1 probed by SEIRA and electrochemical impedance spectroscopy.
DOI: 10.1039/C4CP00167B