The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases.
Samuel H SchneiderJacek KozuchSteven G BoxerPublished in: ACS central science (2021)
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.
Keyphrases
- escherichia coli
- genome wide
- amino acid
- multidrug resistant
- molecular dynamics
- klebsiella pneumoniae
- gram negative
- physical activity
- body composition
- visible light
- structural basis
- electronic health record
- single cell
- density functional theory
- gene expression
- protein protein
- molecular dynamics simulations
- small molecule
- highly efficient
- machine learning
- big data
- binding protein
- raman spectroscopy
- energy transfer