2020
DOI: 10.1371/journal.pone.0233509
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Predicting the viability of beta-lactamase: How folding and binding free energies correlate with beta-lactamase fitness

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 β-lactamase folding free energies and use this data in c… Show more

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Cited by 28 publications
(27 citation statements)
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“…With regard to MD simulations, we find the strongest correlations between simulation observables and the experimental properties of thermal stability and KM. This appears to be in line with past results in which computational techniques predict thermal stability more easily than catalytic activity [72,73]. The finding that increased hydrophobic surface area on helix residues strongly correlates with increased thermal stability is curious.…”
Section: Discussionsupporting
confidence: 88%
“…With regard to MD simulations, we find the strongest correlations between simulation observables and the experimental properties of thermal stability and KM. This appears to be in line with past results in which computational techniques predict thermal stability more easily than catalytic activity [72,73]. The finding that increased hydrophobic surface area on helix residues strongly correlates with increased thermal stability is curious.…”
Section: Discussionsupporting
confidence: 88%
“…While “ampicillin, 2500 μg/mL” [Stiffler et al, 2015] has been the ground truth assay of choice for previous work using unsupervised models to infer mutation effect for β ℓ [Hopf et al, 2017, Riesselman et al, 2018], and correlates strongly with “ampicillin, fitness” [Firnberg et al, 2014] and “amoxicillin, MIC” [Jacquier et al, 2013], it negatively correlates with “ampicillin, ΔΔG stat ” [Deng et al, 2012], and variably correlates with the same assay from the same paper but at lower concentrations “ampicillin [39, 156, 625] μg/mL” [Stiffler et al, 2015]. Similarly, if the consideration is instead how a mutation impacts β ℓ ’s ability to hydrolyze “cefotaxime, 0.15 μg/mL”, a different β -lactam antibiotic [Stiffler et al, 2015], or thermostability [Yang et al, 2020] - the outcomes also vary.…”
Section: Datamentioning
confidence: 99%
“…Both the test systems in this study were previously used by our lab to predict ∆∆G values for the same eight mutations using the non-rigorous methods FoldX and MD+FoldX, and rigorous coarsegrained umbrella sampling MD simulations. 56 The pmx with double-system/single-box approach clearly outperforms our previous FoldX 12,13 (1BRS:R 2 =0.59, 3HFM:R 2 =−0.005) and MD+FoldX [57][58][59] (1BRS:R 2 =0.62, 3HFM:R 2 =0.04) estimates in both the complexes. Interestingly, the all-atom pmx with double-system/single-box approach in both the complexes performs similarly to our previous coarse-grained (1BRS:R 2 =0.85, 3HFM:R 2 =0.35) method.…”
Section: Resultsmentioning
confidence: 69%