Journal ArticleDOI
Darwinian evolution can follow only very few mutational paths to fitter proteins.
TLDR
It is demonstrated that 102 mutational trajectories linking β-lactamase alleles are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, which implies that the protein tape of life may be largely reproducible and even predictable.Abstract:
Five point mutations in a particular β-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of ∼100,000. In principle, evolution to this high-resistance β-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the β-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.read more
Citations
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Engineering the third wave of biocatalysis
Uwe T. Bornscheuer,Gjalt W. Huisman,Romas J. Kazlauskas,Romas J. Kazlauskas,Stefan Lutz,Jeffrey C. Moore,Karen Robins +6 more
TL;DR: Applications of protein-engineered biocatalysts ranging from commodity chemicals to advanced pharmaceutical intermediates that use enzyme catalysis as a key step are discussed.
Journal ArticleDOI
Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems.
TL;DR: There is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner with the advent of high-throughput functional genomics.
Journal ArticleDOI
Enzyme Promiscuity: A Mechanistic and Evolutionary Perspective
Olga Khersonsky,Dan S. Tawfik +1 more
TL;DR: The hypothesis that promiscuous enzymatic activities serve as evolutionary starting points and highlight the unique evolutionary features ofpromiscuous enzyme functions are addressed.
Journal ArticleDOI
Exploring protein fitness landscapes by directed evolution
TL;DR: Directed evolution studies have shown how rapidly some proteins can evolve under strong selection pressures and, because the entire 'fossil record' of evolutionary intermediates is available for detailed study, they have provided new insight into the relationship between sequence and function.
Journal ArticleDOI
Stability effects of mutations and protein evolvability
Nobuhiko Tokuriki,Dan S. Tawfik +1 more
TL;DR: Way of predicting and analyzing stability effects of mutations, and mechanisms that buffer or compensate for these destabilizing effects and thereby promote protein evolvabilty, in nature and in the laboratory are described.
References
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Journal ArticleDOI
Rapid evolution of a protein in vitro by DNA shuffling.
TL;DR: It is reported here that selected mutants had a minimum inhibitory concentration of 640 μg ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme.
Journal ArticleDOI
The genetic theory of adaptation: a brief history
TL;DR: The history of adaptation theory is surveyed, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation.
Journal ArticleDOI
A standard numbering scheme for the class A beta-lactamases.
Book
Antibiotics: Actions, Origins, Resistance
TL;DR: This new text offers a comprehensive, up to date account of those structural classes of antibiotics that have had an impact in human infectious disease.
Journal ArticleDOI
Missense meanderings in sequence space: a biophysical view of protein evolution
TL;DR: This work reviews the literature on biophysics as it relates to molecular evolution and advances a biophysical model of protein evolution that helps to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate ofprotein evolution.