Apr 16, 2020

Predicting the Viability of Beta-Lactamase: How Folding and Binding Free Energies Correlate with Beta-Lactamase Fitness

BioRxiv : the Preprint Server for Biology
J. YangBrenda M. Rubenstein

Abstract

One of the long-standing holy grails of molecular evolution has been the ability to predict an organism's fitness directly from its genotype. With such predictive abilities in hand, researchers would be able to more accurately forecast how organisms will evolve and how proteins with novel functions could be engineered, leading to revolutionary advances in medicine and biotechnology. In this work, we assemble the largest reported set of experimental TEM-1 {beta}-lactamase folding free energies and use this data in conjunction with previously acquired fitness data and computational free energy predictions to determine how much of the {beta}-lactamase can be directly predicted by thermodynamic folding and binding free energies. We focus upon {beta}-lactamase because of its long history as a model enzyme and its central role in antibiotic resistance. Based upon a set of 21 {beta}-lactamase single and double mutants expressly designed to influence protein folding, we first demonstrate that modeling software such as FoldX and PyRosetta designed to compute folding free energies can meaningfully, although not perfectly, predict the experimental folding free energies of single mutants. Interestingly, while these techniques also yield se...Continue Reading

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Mentioned in this Paper

Study
Biochemical Pathway
Microarray Analysis
The Cancer Genome Atlas
Genome
Genes
Neoplasms
Cross Validation
Molecular Profiling
Profile (Lab Procedure)

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