Predicting allostery and microbial drug resistance with molecular simulations

Current Opinion in Structural Biology
George A Cortina, Peter M Kasson

Abstract

Beta-lactamase enzymes mediate the most common forms of gram-negative antibiotic resistance affecting clinical treatment. They also constitute an excellent model system for the difficult problem of understanding how allosteric mutations can augment catalytic activity of already-competent enzymes. Multiple allosteric mutations have been identified that alter catalytic activity or drug-resistance spectrum in class A beta lactamases, but predicting these in advance continues to be challenging. Here, we review computational techniques based on structure and/or molecular simulation to predict such mutations. Structure-based techniques have been particularly helpful in developing graph algorithms for analyzing critical residues in beta-lactamase function, while classical molecular simulation has recently shown the ability to prospectively predict allosteric mutations increasing beta-lactamase activity and drug resistance. These will ultimately achieve the greatest power when combined with simulation methods that model reactive chemistry to calculate activation free energies directly.

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Citations

Aug 1, 2020·Frontiers in Molecular Biosciences·Gennady M VerkhivkerPeng Tao
Jul 30, 2019·Frontiers in Molecular Biosciences·Feng WangPeng Tao
Dec 7, 2018·International Journal of Molecular Sciences·Tushar Modi, S Banu Ozkan
Apr 4, 2021·International Journal of Molecular Sciences·Bethany Kolbaba-KartchnerS Banu Ozkan
Apr 7, 2020·Journal of Chemical Theory and Computation·Peter T LakeMartin McCullagh

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