Protein polarization effects in the thermodynamic computation of vibrational Stark shifts

Richard, Alissa; Gascón, José A.

doi:10.1007/s00214-019-2522-2

Cited by 7 publications

(6 citation statements)

References 40 publications

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“…While it is tempting to directly calculate the active site electric field as experienced by the β-lactam C=O in the MD simulations, accurate calculation of electric fields when short H-bonds are involved in catalysis requires more advanced simulation force fields and levels of theory. 42 − 47 …”

Section: Resultsmentioning

confidence: 99%

“…Comparison of the commonly observed conformations, for both the S70G and E166N mutants and the respective WT proteins, enables a structure-guided approach to interpret the IR and kinetic results as discussed below. While it is tempting to directly calculate the active site electric field as experienced by the β-lactam CO in the MD simulations, accurate calculation of electric fields when short H-bonds are involved in catalysis requires more advanced simulation force fields and levels of theory. − …”

Section: Resultsmentioning

confidence: 99%

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The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

2021

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The interplay of enzyme active site electrostatics and chemical positioning is important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 toward extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure–function paradigm and noncovalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rates and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that this evolutionary trajectory utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

2021

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“…The correspondence between vibrational solvatochromism and MD simulations is supported by experimental results from vibrational Stark spectroscopy (VSS), ,, which allows for independent determination of the Stark tuning rate in a defined externally applied electric field and supports the application of the linear VSE (eq ). Further support is obtained by experiments demonstrating a solvent-independent anharmonicity as well as simulations at higher levels of theory using polarizable (POL) force fields, DFT, and QM/MM simulations. ,− …”

Section: Introductionmentioning

confidence: 87%

Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

et al. 2021

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Non-covalent 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 towards 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 electrics fields are correlated to conformation-dependent effects of the flexible PenG side-chain, including both local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in 3-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.

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“…The TS stabilization mechanism is also supported by catalysis powered by electrostatic interactions. 16–19 For example, the enzyme–substrate electrostatic interactions of the substrate oxygen atom in the isomerization of 5-androstene-3,17-dione (5-AND) catalyzed by ketosteroid isomerase (KSI) (Fig. S1 † ) reduce the Δ G ‡ of the reaction, and are extensively reported as supporting the electrostatic TS stabilization mechanism.…”

Section: Introductionmentioning

confidence: 99%

Key difference between transition state stabilization and ground state destabilization: increasing atomic charge densities before or during enzyme–substrate binding

Chen

et al. 2022

Chem. Sci.

102

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Protein polarization effects in the thermodynamic computation of vibrational Stark shifts

Cited by 7 publications

References 40 publications

The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

Key difference between transition state stabilization and ground state destabilization: increasing atomic charge densities before or during enzyme–substrate binding

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