De novo protein design: fully automated sequence selection.

  title={De novo protein design: fully automated sequence selection.},
  author={Bassil I. Dahiyat and Stephen L. Mayo},
  volume={278 5335},
The first fully automated design and experimental validation of a novel sequence for an entire protein is described. A computational design algorithm based on physical chemical potential functions and stereochemical constraints was used to screen a combinatorial library of 1.9 x 10(27) possible amino acid sequences for compatibility with the design target, a betabetaalpha protein motif based on the polypeptide backbone structure of a zinc finger domain. A BLAST search shows that the designed… 
De novo protein design: towards fully automated sequence selection.
This work designed 20 out of 28 positions in the test motif of the betabetaalpha motif typified by the zinc finger DNA binding module to test the design methodology and found it to be folded with a weakly cooperative thermal unfolding transition.
De novo protein design. I. In search of stability and specificity.
A fully automated protein design strategy that works on the entire sequence of the protein and uses a full atom representation, and it is shown that each additional term of the energy function improves the performance of the design procedure.
11 Computational Protein Design
  • Chemistry
This chapter introduces the automated protein design and experimental validation of a novel designed sequence, as described in Dahiyat and Mayo [1]. Given a three-dimensional (3D) backbone structure,
An Evolution-Based Approach to De Novo Protein Design and Case Study on Mycobacterium tuberculosis
The method was tested on a computational folding experiment based on a large set of 87 protein structures covering different fold classes, which showed that the evolution-based design significantly enhances the foldability and biological functionality of the designed sequences compared to the traditional physics-based force field methods.
Applications of computational protein design
The diverse applications of computational protein design with ORBIT (Optimization of Rotamers by Iterative Techniques) are reported, and an important residue position capable of modulating the agonist specificity of the mouse muscle nicotinic acetylcholine receptor (nAChR) is identified.
In Silico Protein Design: A Combinatorial and Global Optimization Approach
While the grand challenge of protein folding is to understand how a particular protein, defined by its amino acid sequence, finds its unique three-dimensional structure, protein design involves the discovery of sets of amino acid sequences that form functional proteins and fold into specific target structures.
De novo protein design. II. Plasticity in sequence space.
A new approach for protein sequence design is developed, which optimizes the complete sequence of a protein based on the knowledge of its backbone structure, its amino acid composition and a physical energy function including van der Waals interactions, electrostatics, and environment free energy.
In silico protein design by combinatorial assembly of protein building blocks
A de novo computational algorithm is proposed that implements a strategy of designing a protein using relatively stable fragments, with a high population time, to engineer new naturally occurring folds with low homology to existing proteins.


Protein design automation
We have conceived and implemented a cyclical protein design strategy that couples theory, computation, and experimental testing. The combinatorially large number of possible sequences and the
De novo design of the hydrophobic cores of proteins
A novel computational approach for the de novo design of hydrophobic cores using a genetic algorithm to globally optimize for a low energy core sequence and structure, using the custom rotamer library as input.
Economy in Protein Design: Evolution of a Metal-Independent ββα Motif Based on the Zinc Finger Domains
An iterative design process involving the synthesis and structural analyses of five polypeptides patterned after the zinc finger domains has led to the development of a metal-independent folded ββα motif, BBA1.
Coupling backbone flexibility and amino acid sequence selection in protein design
  • A. Su, S. L. Mayo
  • Physics
    Protein science : a publication of the Protein Society
  • 1997
This result demonstrates that backbone flexibility can be combined explicitly with amino acid side‐chain selection and that the selection algorithm is sufficiently robust to tolerate perturbations as large as 15% of Gβ1's native supersecondary structure parameter values.
Controlling topology and native-like behavior of de novo-designed peptides: design and characterization of antiparallel four-stranded coiled coils.
These results reinforce the importance of optimizing van der Waals packing interactions in protein design but demonstrate that hydrophobic packing must be balanced with hydrogen-bonding and electrostatic interactions to produce novel native-like proteins.
Probing the role of packing specificity in protein design.
  • B. Dahiyat, S. L. Mayo
  • Materials Science
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
By using a protein-design algorithm that quantitatively considers side-chain packing, the effect of specific steric constraints on protein design was assessed in the core of the streptococcal protein G beta1 domain and an analysis of the modeled protein structures suggested that penalizing for exposed hydrophobic surface area can improve design performance.
The dead-end elimination theorem and its use in protein side-chain positioning
Application of the 'dead-end elimination' theorem effectively controls the computational explosion of the rotamer combinatorial problem, thereby allowing the determination of the global minimum energy conformation of a large collection of side chains.
Sequence space, folding and protein design.
Novel metal-binding proteins by design
The results indicate that the designed proteins bind Zn(II) with high affinity and tetrahedral coordination geometry, and that the overall secondary and tertiary structure of the B1 domain is maintained.