The construction of new proteins: V. A template‐assembled synthetic protein (TASP) containing both a 4‐helix bundle and β‐barrel‐like structure

Mutter, Manfred; Hersperger, René; Gubernator, K.; Müller, Klaus

doi:10.1002/prot.340050104

Cited by 58 publications

(26 citation statements)

References 33 publications

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“…We are now actively trying to find them again in the test-tube. a) Side view of a template-assembled "two-domain" protein model [174] (T8-(4z)(4p) in Fig. 12) (template in blue, lysine side chains in yellow, four-helix-bundle structure in red.…”

Section: Prospects and Challenges In Protein Design By Chemical Methodsmentioning

confidence: 99%

A Chemical Approach to Protein Design—Template‐Assembled Synthetic Proteins (TASP)

Mutter

Vuilleumier

1989

Angew. Chem. Int. Ed. Engl.

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406

157

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Advances in methodology in both chemistry and molecular biology allow us to take a fresh look at protein science. Chemical synthesis of peptides and site-directed mutagenesis are now standard research tools, paving the way for the construction of new proteins with tailor-made structural and functional properties. The decisive hurdle on the way lies not in the synthesis of the molecules proper but rather in a better understanding of the complex folding pathways of polypeptide chains into spatially well-defined structures. Can the chemist use his synthetic tools to bypass the notorious "folding problem?" In this article, we present a new approach developed in our laboratory, which opens a chemical route to artificial proteins with predetermined three-dimensional structures, allowing a first step towards the synthesis of new proteins with functional properties.

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Section: Prospects and Challenges In Protein Design By Chemical Methodsmentioning

confidence: 99%

A Chemical Approach to Protein Design—Template‐Assembled Synthetic Proteins (TASP)

Mutter

Vuilleumier

1989

Angew. Chem. Int. Ed. Engl.

Self Cite

406

157

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“…Having already observed Cl -selectivity in synthetic phospholipid bilayers (Reddy et al, 1993) with the M2 segment from the glycine receptor as both the free peptide (M2GlyR) and as a four-helix bundle (T 4 -M2GlyR) built with a template strategy (Mutter et al, 1989;Iwamoto et al, 1994), this sequence was an obvious choice to begin studying its effects on epithelial monolayers. Due to the complexity of synthesizing and purifying the template sequence, the studies focused on the more tractable monomeric form.…”

Section: M2glyr Studiesmentioning

confidence: 99%

Channel Replacement Therapy for Cystic Fibrosis

Tomich¹,

Bukovnik²,

Layman³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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“…This step helps minimize the contact cost. For example, the monomer pairs (1,8) and (11,14) in Fig. 2a are such residues.…”

Section: Rules For Designing Sequencesmentioning

confidence: 99%

“…Recently there have been major advances in protein design [i.e., in the design of amino acid sequences that will fold to desired "target" native conformations (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)]. However, the following several hurdles remain to be overcome.…”

mentioning

confidence: 99%

Inverse protein folding problem: designing polymer sequences.

Yue

Dill

1992

Proc. Natl. Acad. Sci. U.S.A.

177

103

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We consider the question of how to design proteins. How can we find "good" amino acid sequences (D) that fold to a desired "target" structure as a native conformation of lowest accessible free energy and (ii) that will not simultaneously fold to many other conformations of the same free energy? Current protein designs often focus on helix propensities and turns. We focus here on designing the hydrophobicity. For a model of self-avoiding hydrophobic/polar chains on two-dimensional square lattices, geometric proofs and exhaustive enumerations show the following results. (i) The strategy hydrophobic residues inside/polar residues outside is not optimal. Placement of additional hydrophobic residues on the surface is often necessary. (u) To avoid unwanted conformations, the designed sequence must have neither too many nor too few hydrophobic residues. (iii) The computational complexity of inverse folding appears to be in a different class than folding: unlike the folding problem, the design problem does not scale exponentially with chain length. Some design strategies, described here for the lattice model, produce good sequences and scale only linearly with chain length.Recently there have been major advances in protein design [i.e., in the design of amino acid sequences that will fold to desired "target" native conformations (1-11)]. However, the following several hurdles remain to be overcome. (i) So far, most designed proteins have only simple symmetries-4-helix bundles and all-sheet conformations, for example (2-4, 9, 10).(ii) Most of the "rational" aspects of design currently focus on the interactions among the "connected" neighbors [i.e., on the intrinsic propensities of monomeric and dimeric amino acids to form helices and turns (12-16)]. However, major forces of folding are due to hydrophobic and other "nonlocal" interactions [i.e., among monomers far apart in the sequence (17-19)]. The main design principle currently used for them is hydrophobic (H) residues inside/polar (P) residues outside. Nevertheless, many real proteins have exposed nonpolar and buried polar units (20,21), and some single-site mutations contradict the hydrophobic residues inside/pol~ar residues outside principle (22). Are there more subtle principles that are important? (iii) A major design problem has been how to avoid simultaneous folding to wrong conformations; designed sequences sometimes appear to fold to "gemiche" states, involving multiple or wrong native structures (ref. 4 and T. Handel, personal communication). It is not known how to control the multiplicity of stable structures (i.e., how to design the desired structure uniquely into the sequence). The problem of sequence design is the "inverse protein folding" problem (23)(24)(25). Whereas the input of a protein folding algorithm would be an amino acid sequence and the output would be a native structure, the input for an inverse folding algorithm would be a desired native structure and the output would be a sequence that will fold to it. Can heuristic rules be f...

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The construction of new proteins: V. A template‐assembled synthetic protein (TASP) containing both a 4‐helix bundle and β‐barrel‐like structure

Cited by 58 publications

References 33 publications

A Chemical Approach to Protein Design—Template‐Assembled Synthetic Proteins (TASP)

A Chemical Approach to Protein Design—Template‐Assembled Synthetic Proteins (TASP)

Channel Replacement Therapy for Cystic Fibrosis

Inverse protein folding problem: designing polymer sequences.

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