Design of a Novel Globular Protein Fold with Atomic-Level Accuracy

  title={Design of a Novel Globular Protein Fold with Atomic-Level Accuracy},
  author={Brian Kuhlman and Gautam Dantas and Gregory C. Ireton and Gabriele Varani and Barry L. Stoddard and David Baker},
  pages={1364 - 1368}
A major challenge of computational protein design is the creation of novel proteins with arbitrarily chosen three-dimensional structures. Here, we used a general computational strategy that iterates between sequence design and structure prediction to design a 93-residue α/β protein called Top7 with a novel sequence and topology. Top7 was found experimentally to be folded and extremely stable, and the x-ray crystal structure of Top7 is similar (root mean square deviation equals 1.2 angstroms) to… 
Computer-based design of novel protein structures.
A variety of methods for generating protein-like scaffolds and for optimizing the protein backbone in conjunction with the amino acid sequence have been developed and have been used to design proteins from scratch and to explore sequence space for naturally occurring protein folds.
Using AlphaFold for Rapid and Accurate Fixed Backbone Protein Design
A rapid and effective approach for fixed backbone computational protein design, leveraging the predictive power of AlphaFold and supported by the structure predictions of other supervised methods as well as ab initio folding.
Computational protein design and discovery
This review discusses some of the major developments in computational protein design, focusing on common inputs to the calculation and several often used search methods.
Computational design of structured loops for new protein functions
This work will describe the progress that has been made on this problem and discuss how recent advances in the field of loop structure prediction can be harnessed and applied to the inverse problem of computational loop design.
TEN Evolution-Based Design of Proteins
This work describes an approach for systematically testing an architecture for natural proteins in which amino acids are engaged in a sparse, hierarchical pattern of interactions in the tertiary structure by computational design of synthetic sequences that gradually add or remove constraints along the hierarchy of interacting residues.


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.
De novo protein design: fully automated sequence selection.
The first fully automated design and experimental validation of a novel sequence for an entire protein is described, and a BLAST search shows that the designed sequence, full sequence design 1 (FSD-1), has very low identity to any known protein sequence.
Accurate computer-based design of a new backbone conformation in the second turn of protein L.
The rational design of loops and turns is a key step towards creating proteins with new functions and in contrast to wild-type protein L the second beta-turn appears to be formed at the rate limiting step in folding.
High-resolution protein design with backbone freedom.
The de novo design of a family of alpha-helical bundle proteins with a right-handed superhelical twist is described, where the overall protein fold was specified by hydrophobic-polar residue patterning, whereas the bundle oligomerization state, detailed main-chain conformation, and interior side-chain rotamers were engineered by computational enumerations of packing in alternate backbone structures.
Prediction of amino acid sequence from structure
Overall, the analysis suggests that statistical profile scores of designed sequences are a novel and valuable figure of merit for assessing and improving protein design algorithms.
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.
Thoroughly sampling sequence space: Large‐scale protein design of structural ensembles
The results of a broad exploration of sequence space, with backbone flexibility, through a novel approach: large‐scale protein design to structural ensembles suggest that the diversity of designed sequences is primarily determined by a structure's overall fold, and that the designability principle postulated from studies of simple models holds in real proteins.
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.