Role of conformational dynamics in the evolution of novel enzyme function

Maria-Solano, Miguel A.; Serrano-Hervás, Eila; Romero‐Rivera, Adrian; Iglésias-Fernández, Javier; Osuna, Sílvia

doi:10.1039/c8cc02426j

Cited by 144 publications

(185 citation statements)

References 164 publications

(123 reference statements)

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“…Next, the behavior of protein variants can be closely followed by MD simulations, allowing for the identification, ranking, and selection of promising candidates for experimental validation [42]. In recent years, efforts towards the possibility of also exploiting more distal positions during protein engineering have been gaining momentum [43][44][45][46][47]. By allosteric action, mutations at these positions often affect the preference of proteins to adopt a dominant conformational state, enabling the engineering of proteins with altered selectivity [48,49] or even adopting novel functions [50,51].…”

Section: Introductionmentioning

confidence: 99%

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Surpeta

Sequeiros-Borja

Brezovský

2020

IJMS

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Computational prediction has become an indispensable aid in the processes of engineering and designing proteins for various biotechnological applications. With the tremendous progress in more powerful computer hardware and more efficient algorithms, some of in silico tools and methods have started to apply the more realistic description of proteins as their conformational ensembles, making protein dynamics an integral part of their prediction workflows. To help protein engineers to harness benefits of considering dynamics in their designs, we surveyed new tools developed for analyses of conformational ensembles in order to select engineering hotspots and design mutations. Next, we discussed the collective evolution towards more flexible protein design methods, including ensemble-based approaches, knowledge-assisted methods, and provable algorithms. Finally, we highlighted apparent challenges that current approaches are facing and provided our perspectives on their further development.

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Section: Introductionmentioning

confidence: 99%

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Surpeta

Sequeiros-Borja

Brezovský

2020

IJMS

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“…Much debated is the existence of a link between active site dynamics and the chemical step 18,19 Some studies have suggested that mutations remote from the enzyme active site may directly impact the energetically accessible conformational states, thereby influencing catalysis [20][21][22] . This has been shown by means of crystal structures and NMR spectra of mutants along evolutionary pathways 20,23,24 together with computational assistance [25][26][27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Molecular Dynamics (MD) simulations allow the reconstruction of the enzyme conformational landscape, and how this is altered by mutations introduced by laboratory evolution [28][29][30] . Tuning the enzyme conformational dynamics has been recently identified as key for novel activity 21,24,[29][30][31] . 4 Understanding the connection between conformational dynamics and epistasis has been limited to a few model enzymes (mainly beta-lactamases) and a single protein trait (usually activity) as a measure of fitness (this term originally refers to the reproductive success of organisms but it can be applied to protein activity, selectivity or stability) [32][33][34][35] .…”

Section: Introductionmentioning

confidence: 99%

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Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

Acevedo‐Rocha

D’Amore

et al. 2020

Preprint

Self Cite

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Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. Yet such efforts are rare and focus only on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report the first multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio-and stereoselective hydroxylation of a steroid. We developed a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative sign and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and beta-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers lessons for engineering P450s.

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“…These small conformational variations are nonetheless sufficient to support enzymatic activity, and inversely, slightly disrupting a protein's structure can greatly affect its biological function [5,6]. As a consequence, current de novo protein design strategies do not only involve the production of a particular fold, but also need to take into account protein dynamics, if one wants to achieve a specific function [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

Sacquin-Mora

2019

J. R. Soc. Interface.

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Dynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein's internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all-atom classic molecular dynamics simulations and coarse-grain calculations of the resulting conformational ensemble mechanical properties. Here, we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy experiments are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.

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Role of conformational dynamics in the evolution of novel enzyme function

Cited by 144 publications

References 164 publications

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

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