Protein Design: The Choice of de Novo Sequences

Beasley, James R.; Hecht, Michael H.

doi:10.1074/jbc.272.4.2031

Cited by 97 publications

(88 citation statements)

References 56 publications

(44 reference statements)

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“…To evaluate the energy of a sequence on each configuration, we associate a hydrophobicity h i with each amino acid of the sequence. In practice, we assign a hydrophobicity which is either 0 (Polar) or 1 (Hydrophobic) to each monomer to create an HP-sequence [26]; that this is a reasonable simplification finds support in the work of Hecht and co-workers [1] (cf. …”

Section: Designabilitymentioning

confidence: 99%

“…We randomly choose 4,000,000 sequences h = (h 1 , · · · , h N ), where h i ∈ [0, 1], and evaluate their energy for all configurations using equation (1). In Fig.…”

Section: Hp Sequencesmentioning

confidence: 99%

“…The de novo design of proteins-an object of enormous activity in recent years [1][2][3][4][5][6][7][8]-has so far dealt primarily with the redesign of known protein folds. Two major accomplishments in the direction of designing a fold that is distinct from known natural folds are the synthesis of a right-handed coiled coil [9] and the synthesis of a zinc finger without zinc [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Emergence of highly designable protein‐backbone conformations in an off‐lattice model

Miller¹,

Zeng²,

Wingreen³

et al. 2002

Proteins

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Despite the variety of protein sizes, shapes, and backbone configurations found in nature, the design of novel protein folds remains an open problem. Within simple lattice models it has been shown that all structures are not equally suitable for design. Rather, certain structures are distinguished by unusually high designability: the number of amino-acid sequences for which they represent the unique ground state; sequences associated with such structures possess both robustness to mutation and thermodynamic stability. Here we report that highly designable backbone conformations also emerge in a realistic off-lattice model. The highly designable conformation of a chain of 23 amino acids are identified, and found to be remarkably insensitive to model parameters. While some of these conformations correspond closely to known natural protein folds, such as the zinc finger and the helix-turn-helix motifs, others do not resemble known folds and may be candidates for novel fold design.2

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Section: Designabilitymentioning

confidence: 99%

“…We randomly choose 4,000,000 sequences h = (h 1 , · · · , h N ), where h i ∈ [0, 1], and evaluate their energy for all configurations using equation (1). In Fig.…”

Section: Hp Sequencesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Emergence of highly designable protein‐backbone conformations in an off‐lattice model

Miller¹,

Zeng²,

Wingreen³

et al. 2002

Proteins

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“…[1][2][3][4] This observation has lead to a strategy for the design of de novo proteins based on the choice of amino acid sequences whose pattern of polar and nonpolar amino acids insures that hydrophobic residues will be buried on folding into the target structure. [3][4][5][6][7][8][9][10][11][12] Other considerations, such as secondary structure propensity, geometric packing, shape complementarity, salt-bridge specificity, and negative design can also play a role in further narrowing (optimizing) the sequences considered in the design process. 10,[13][14][15][16][17][18] Hecht and collaborators used a combinatorial approach to design a set of de novo amino acid sequences with the four-helix bundle as the target structure.…”

Section: Introductionmentioning

confidence: 99%

Relative stability of de novo four–helix bundle proteins: Insights from coarse grained molecular simulations

2011

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We use a recently developed coarse-grained computational model to investigate the relative stability of two different sets of de novo designed four-helix bundle proteins. Our simulations suggest a possible explanation for the experimentally observed increase in stability of the four-helix bundles with increasing sequence length. In details, we show that both short subsequences composed only by polar residues and additional nonpolar residues inserted, via different point mutations in ad hoc positions, seem to play a significant role in stabilizing the fourhelix bundle conformation in the longer sequences. Finally, we propose an additional mutation that rescues a short amino acid sequence that would otherwise adopt a compact misfolded state. Our work suggests that simple computational models can be used as a complementary tool in the design process of de novo proteins.

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“…Today, the eld is developing faster and faster, thanks to the involvement of advanced computer algorithms for designing and optimization of structures. In 1997, in their mini-review of protein design, Beasley and Hecht pointed out several problems, as β-sheet and mixed structured construction, as well as incorporation of thermodynamics, structural and functional properties of natural proteins, and nally getting enzymatic activity [5].…”

Section: Introductionmentioning

confidence: 99%

De Novo Designed Proteins - Perspective Materials for Nanotechnology

Grzyb

2012

Acta Phys. Pol. A

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The paper explores the eld of de novo protein design, as a source of material for eective hybrid nanostructures. Main design approaches, namely the intuitional and the computational strategy, are briey overviewed. The achievements in the eld are illustrated with several examples, starting from historical heme binding maquettes to novel non-natural enzymes. Separate paragraph covers the problem of designing peptides, which may act as anchor between biological and non-biological parts of nanostructures. The advantages of de novo designed proteins and still existing problems of the eld are discussed.

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Protein Design: The Choice of de Novo Sequences

Cited by 97 publications

References 56 publications

Emergence of highly designable protein‐backbone conformations in an off‐lattice model

Emergence of highly designable protein‐backbone conformations in an off‐lattice model

Relative stability of de novo four–helix bundle proteins: Insights from coarse grained molecular simulations

De Novo Designed Proteins - Perspective Materials for Nanotechnology

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