Computational Design of Four-Helix Bundle Proteins That Bind Nonbiological Cofactors

Lehmann, Andreas; Saven, Jeffery G.

doi:10.1021/bp070178q

Cited by 9 publications

(6 citation statements)

References 85 publications

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“…Although a detailed understanding of protein folding, evolution, and design remains elusive, it is generally acknowledged that gene duplication and fusion is the likely evolutionary process responsible for the emergence of common symmetric protein architecture from simpler peptide motifs (McLachlan, 1972;Ohno, 1970). Symmetry is also a strategy to substantially simplify and parameterize computational methods for efficient de novo protein design (Bellesia et al, 2010;Fortenberry et al, 2011;Kuhlman et al, 2003;Lehmann and Saven, 2008;Richter et al, 2010) and exact symmetry of protein primary and tertiary structure has been experimentally shown to confer robust foldability in the face of major structural rearrangements (Longo et al, 2013). Despite the prevalence of symmetry in protein tertiary structure, a clear understanding of the role of symmetry in protein evolution, as well as the development of practical symmetric design principles (e.g., principles that can leverage the simplifying power of symmetry with the nucleation condensation mechanism of protein folding) are lacking.…”

Section: Introductionmentioning

confidence: 99%

Evolution and Design of Protein Structure by Folding Nucleus Symmetric Expansion

et al. 2014

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Models of symmetric protein evolution typically invoke gene duplication and fusion events, in which repetition of a structural motif generates foldable, stable symmetric protein architecture. Success of such evolutionary processes suggests that the duplicated structural motif must be capable of nucleating protein folding. If correct, symmetric expansion of a folding nucleus sequence derived from an extant symmetric fold may be an elegant and computationally tractable solution to de novo protein design. We report the efficient de novo design of a β-trefoil protein by symmetric expansion of a β-trefoil folding nucleus, previously identified by ɸ-value analysis. The resulting protein, having exact sequence symmetry, exhibits superior folding properties compared to its naturally evolved progenitor-with the potential for redundant folding nuclei. In principle, folding nucleus symmetric expansion can be applied to any given symmetric protein fold (that is, nearly one-third of the known proteome) provided information of the folding nucleus is available.

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Section: Introductionmentioning

confidence: 99%

Evolution and Design of Protein Structure by Folding Nucleus Symmetric Expansion

et al. 2014

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“…Much exciting progress is being made in this de novo design of heme proteins at present 14–20. Heme proteins are being developed as novel biomolecular with non‐linear optical properties, as molecules that self‐assemble at an interface providing an ordered material with electron transfer properties, and as “smart” materials that respond to stimuli such as changes in pH, ionic strength or redox environment 21–29. The design and development of such heme proteins with specific structural and functional properties requires a firm understanding of the heme group and its binding sites in proteins.…”

Section: Introductionmentioning

confidence: 99%

Heme proteins—Diversity in structural characteristics, function, and folding

2010

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The characteristics of heme prosthetic groups and their binding sites have been analyzed in detail in a data set of nonhomologous heme proteins. Variations in the shape, volume, and chemical composition of the binding site, in the mode of heme binding and in the number and nature of heme-protein interactions are found to result in significantly different heme environments in proteins with different functions in biology. Differences are also seen in the properties of the apo states of the proteins. The apo states of proteins that bind heme permanently in their functional form show some disorder, ranging from local unfolding in the heme binding pocket to complete unfolding to give a random coil. In contrast, proteins that bind heme transiently are fully folded in their apo and holo states, presumably allowing both apo and holo forms to remain biologically active resisting aggregation or proteolysis. The principles identified here provide a framework for the design of de novo proteins that will exhibit tight heme ligand binding and for the identification of the function of structural genomic target proteins with heme ligands.

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“…The main structural models used to study the packing effects following fluorination were 4‐helix bundles. This 3‐D arrangement is commonly present in proteins and it has been the topic of extensive de novo design efforts . It has been demonstrated that the hydrophobic core of a 4‐helix bundle can be built from contact interactions between hydrophobic residues at the “a” and “d” positions of a helical heptad (abcdefg) n repeat.…”

Section: Effect Of Fluorination On Enzymatic Stability and Reactivitymentioning

confidence: 99%

Evolution of fluorinated enzymes: An emerging trend for biocatalyst stabilization

Biava

Budiša

2014

Engineering in Life Sciences

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Nature uses remarkably limited sets of chemistries in its repertoire, especially when compared to synthetic organic chemistry. This limits both the chemical and structural diversity that can ultimately be achieved with biocatalysis, unless the powers of chemical synthesis are merged with biological systems by integrating nonnatural synthetic chemistries into the protoplasma of living cells. Of particular interest, here is the fluorous effect that has recently established the potential to generate enzymes with an increased resistance toward both high temperature and organic solvents. For these reasons, we are witnessing a rapid development of efficient methodologies for the incorporation of fluorinated amino acids in protein synthesis, using both in vivo and in vitro strategies. In this review, we highlight relevant and trendsetting results in the design and engineering of stable fluorinated proteins and peptides along with whole‐cell biocatalysis as an economically attractive and convenient application with exclusive focus on industrial biocatalysis. Finally, we envision new strategies to improve current achievements and enable the field to progress far beyond the current state‐of‐the‐art.

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Computational Design of Four-Helix Bundle Proteins That Bind Nonbiological Cofactors

Cited by 9 publications

References 85 publications

Evolution and Design of Protein Structure by Folding Nucleus Symmetric Expansion

Evolution and Design of Protein Structure by Folding Nucleus Symmetric Expansion

Heme proteins—Diversity in structural characteristics, function, and folding

Evolution of fluorinated enzymes: An emerging trend for biocatalyst stabilization

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