Ab Initio Raman Spectra of β-Lactamase Inhibitor Intermediates Bound to E166A SHV β-Lactamase

Area of Science:

• Biochemistry
• Computational Chemistry
• Spectroscopy

Background:

• Bacterial drug resistance is a major global health concern.
• Beta-lactamase enzymes confer resistance to beta-lactam antibiotics.
• Understanding enzyme-inhibitor interactions is crucial for developing new therapeutics.

Purpose of the Study:

• To computationally investigate the structural and vibrational properties of beta-lactamase inhibitors bound to a mutated enzyme.
• To analyze and assign experimental vibrational Raman spectra for enzyme-bound clavulanic acid and tazobactam.
• To assess the accuracy of different computational methods for predicting Raman spectra.

Main Methods:

• Hybrid molecular mechanics/quantum mechanics (QM/MM) simulations were employed.
• Simulations were performed on clavulanic acid and tazobactam intermediates bound to E166A SHV beta-lactamase.
• Raman spectra were analyzed using time autocorrelation function of polarizability and instantaneous normal modes.

Main Results:

• The trans-enamine moiety's stretchings strongly couple with N-H rocking, forming bands between 1600-1640 cm⁻¹.
• Accurate description of Raman scattering requires including mechanical and electrical anharmonicity.
• Environmental electrostatic fields dynamically modulate Raman activity.

Conclusions:

• The study provides insights into the vibrational spectra of enzyme-bound beta-lactamase inhibitors.
• Computational methods, particularly QM/MM, are valuable for analyzing drug resistance mechanisms.
• Understanding anharmonicity and environmental effects is key for accurate spectral prediction.