Automated protein design: Landmarks and operational principles.

Protein design has an eventful history spanning over three decades, with handful of success stories reported, and numerous failures not reported. Design practices have benefited tremendously from improvements in computer hardware and advances in scientific algorithms. Though protein folding problem still remains unsolved, the possibility of having multiple sequence solutions for a single fold makes protein design a more tractable problem than protein folding. One of the most significant advancement in this area is the implementation of automated design algorithms on pre-defined templates or completely new folds, optimized through deterministic and heuristic search algorithms. This progress report provides a succinct presentation of important landmarks in automated design attempts, followed by brief account of operational principles in automated design methods.

[1]  S. L. Mayo,et al.  Enzyme-like proteins by computational design , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J R Desjarlais,et al.  De novo design of the hydrophobic cores of proteins , 1995, Protein science : a publication of the Protein Society.

[3]  V. Malashkevich,et al.  Alternating arginine-modulated substrate specificity in an engineered tyrosine aminotransferase , 1995, Nature Structural Biology.

[4]  C. Sander,et al.  An effective solvation term based on atomic occupancies for use in protein simulations , 1993 .

[5]  N. Metropolis,et al.  Equation of State Calculations by Fast Computing Machines , 1953, Resonance.

[6]  I. Karle,et al.  De novo protein design: crystallographic characterization of a synthetic peptide containing independent helical and hairpin domains. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Goldstein.  Efficient rotamer elimination applied to protein side-chains and related spin glasses. , 1994, Biophysical journal.

[8]  M. Struthers,et al.  Design of a Monomeric 23-Residue Polypeptide with Defined Tertiary Structure , 1996, Science.

[9]  C. Pabo.  Molecular technology: Designing proteins and peptides , 1983, Nature.

[10]  J. W. Neidigh,et al.  Designing a 20-residue protein , 2002, Nature Structural Biology.

[11]  B. Höcker,et al.  PocketOptimizer and the Design of Ligand Binding Sites. , 2016, Methods in molecular biology.

[12]  Christopher A. Voigt,et al.  Trading accuracy for speed: A quantitative comparison of search algorithms in protein sequence design. , 2000, Journal of molecular biology.

[13]  A. Fersht,et al.  Engineering a novel specificity in subtilisin BPN'. , 1993, Biochemistry.

[14]  The link between sequence and conformation in protein structures appears to be stereochemically established. , 2006, The journal of physical chemistry. B.

[15]  G. N. Ramachandran,et al.  Stereochemistry of polypeptide chain configurations. , 1963, Journal of molecular biology.

[16]  D. Engelman,et al.  Design of single-layer β-sheets without a hydrophobic core , 2000, Nature.

[17]  P. S. Kim,et al.  A buried polar interaction can direct the relative orientation of helices in a coiled coil. , 1998, Biochemistry.

[18]  D. Eisenberg,et al.  Atomic solvation parameters applied to molecular dynamics of proteins in solution , 1992, Protein science : a publication of the Protein Society.

[19]  N. Skelton,et al.  Tryptophan zippers: Stable, monomeric β-hairpins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D Eisenberg,et al.  Crystal structure of alpha 1: implications for protein design. , 1990, Science.

[21]  K. Mayo,et al.  A folding pathway for βpep‐4 peptide 33mer: From unfolded monomers and β‐sheet sandwich dimers to well‐structured tetramers , 1998 .

[22]  T. Creamer.  Side‐chain conformational entropy in protein unfolded states , 2000, Proteins.

[23]  Niles A Pierce,et al.  Protein design is NP-hard. , 2002, Protein engineering.

[24]  N. Suzuki,et al.  Optimazation of the loop length for folding of a helix-loop-helix peptide , 1999 .

[25]  M. Jiménez,et al.  De novo design of a monomeric three‐stranded antiparallel β‐sheet , 2008, Protein science : a publication of the Protein Society.

[26]  I. Lasters,et al.  The fuzzy-end elimination theorem: correctly implementing the side chain placement algorithm based on the dead-end elimination theorem. , 1993, Protein engineering.

[27]  S. Durani,et al.  The interplay of sequence and stereochemistry in defining conformation in proteins and polypeptides. , 2006, Biopolymers.

[28]  Urry Dw,et al.  The Gramicidin A Transmembrane Channel: A Proposed π(L,D) Helix , 1971 .

[29]  D. Eisenberg,et al.  Design of three-dimensional domain-swapped dimers and fibrous oligomers. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Ponder,et al.  Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes. , 1987, Journal of molecular biology.

[31]  H. Scheraga,et al.  Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[32]  S. L. Mayo,et al.  Automated design of the surface positions of protein helices , 1997, Protein science : a publication of the Protein Society.

[33]  L. H. Bradley,et al.  Protein design by binary patterning of polar and nonpolar amino acids. , 1993, Methods in molecular biology.

[34]  A. Lustig,et al.  Design of a minimal protein oligomerization domain by a structural approach , 2000, Protein science : a publication of the Protein Society.

[35]  D. Raleigh,et al.  De novo design of helical bundles as models for understanding protein folding and function. , 2000, Accounts of chemical research.

[36]  S. A. Marshall,et al.  Energy functions for protein design. , 1999, Current opinion in structural biology.

[37]  Stephen L Mayo,et al.  One‐ and two‐body decomposable Poisson‐Boltzmann methods for protein design calculations , 2005, Protein science : a publication of the Protein Society.

[38]  D B Gordon,et al.  Branch-and-terminate: a combinatorial optimization algorithm for protein design. , 1999, Structure.

[39]  Chittaranjan Das,et al.  A Designed Three Stranded beta-Sheet Peptide as a Multiple beta-Hairpin Model , 1998 .

[40]  P. Balaram,et al.  Stereochemical control of peptide folding. , 1999, Bioorganic & medicinal chemistry.

[41]  Roland L. Dunbrack,et al.  Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains , 1994, Nature Structural Biology.

[42]  Summer B. Thyme,et al.  Improved modeling of side-chain--base interactions and plasticity in protein--DNA interface design. , 2012, Journal of molecular biology.

[43]  J. Richardson,et al.  The penultimate rotamer library , 2000, Proteins.

[44]  M J Sternberg,et al.  Side‐chain conformational entropy in protein folding , 1995, Protein science : a publication of the Protein Society.

[45]  W. DeGrado,et al.  Solution structure and dynamics of a de novo designed three-helix bundle protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Baker,et al.  Design of a Novel Globular Protein Fold with Atomic-Level Accuracy , 2003, Science.

[47]  A. Schepartz,et al.  Miniature homeodomains: high specificity without an N-terminal arm. , 2003, Journal of the American Chemical Society.

[48]  D. Baker,et al.  Native protein sequences are close to optimal for their structures. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Tanja Kortemme,et al.  Design of a 20-Amino Acid, Three-Stranded β-Sheet Protein , 1998 .

[50]  Roland L. Dunbrack.  Rotamer libraries in the 21st century. , 2002, Current opinion in structural biology.

[51]  C. Pace,et al.  Forces contributing to the conformational stability of proteins , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[52]  K. Dill.  Dominant forces in protein folding. , 1990, Biochemistry.

[53]  Michael R. Shirts,et al.  Atomistic protein folding simulations on the submillisecond time scale using worldwide distributed computing. , 2003, Biopolymers.

[54]  Roland L. Dunbrack,et al.  Backbone-dependent rotamer library for proteins. Application to side-chain prediction. , 1993, Journal of molecular biology.

[55]  S. Gellman,et al.  Influence of Strand Number on Antiparallel β-Sheet Stability in Designed Three- and Four-stranded β-Sheets , 2003 .

[56]  B. Stoddard,et al.  Design, activity, and structure of a highly specific artificial endonuclease. , 2002, Molecular cell.

[57]  Pattabhi,et al.  Configurationally guided peptide conformational motifs: Crystal structure of a (LDLDDL alpha)-D-alpha-L-beta-D-beta-D-alpha-L-beta type hexapeptide fold , 1997 .

[58]  L. Wesson,et al.  Packed protein bilayers in the 0.90 å resolution structure of a designed alpha helical bundle , 1999, Protein science : a publication of the Protein Society.

[59]  S. Durani,et al.  Stereospecific peptide folds. A rationally designed molecular bracelet. , 2004, Chemical communications.

[60]  S J Wodak,et al.  Automatic protein design with all atom force-fields by exact and heuristic optimization. , 2000, Journal of molecular biology.

[61]  J. Watson,et al.  A novel main-chain anion-binding site in proteins: the nest. A particular combination of phi,psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions. , 2002, Journal of molecular biology.

[62]  R. MacKinnon,et al.  Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors , 2001, Nature.

[63]  J. Watson,et al.  The conformations of polypeptide chains where the main-chain parts of successive residues are enantiomeric. Their occurrence in cation and anion-binding regions of proteins. , 2002, Journal of molecular biology.

[64]  Paul T. Matsudaira,et al.  NMR structure of the 35-residue villin headpiece subdomain , 1997, Nature Structural Biology.

[65]  G. N. Ramachandran,et al.  Conformation of polypeptides and proteins. , 1968, Advances in protein chemistry.

[66]  K. Dill,et al.  Hydrogen bonding in globular proteins. , 1992, Journal of molecular biology.

[67]  I. Karle,et al.  Solid state and solution conformations of a helical peptide with a central gly‐gly segment , 1996, Biopolymers.

[68]  W. V. van Gunsteren,et al.  An efficient mean solvation force model for use in molecular dynamics simulations of proteins in aqueous solution. , 1996, Journal of molecular biology.

[69]  J. Ippolito,et al.  Hydrogen bond stereochemistry in protein structure and function. , 1990, Journal of molecular biology.

[70]  A R Leach,et al.  Exploring the conformational space of protein side chains using dead‐end elimination and the A* algorithm , 1998, Proteins.

[71]  P. S. Kim,et al.  A switch between two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants. , 1993, Science.

[72]  A. Fersht,et al.  Variants of subtilisin BPN' with altered specificity profiles. , 1994, Biochemistry.

[73]  W. DeGrado.  Design of peptides and proteins. , 1988, Advances in protein chemistry.

[74]  I Lasters,et al.  Computation of the binding of fully flexible peptides to proteins with flexible side chains , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[75]  S. L. Mayo,et al.  Conformational splitting: A more powerful criterion for dead‐end elimination , 2000, J. Comput. Chem..

[76]  K. Weeks,et al.  Assembly of a Ribonucleoprotein Catalyst by Tertiary Structure Capture , 1996, Science.

[77]  E. Blout,et al.  The conformation of gramicidin A. , 1974, Biochemistry.

[78]  Yi Liu,et al.  RosettaDesign server for protein design , 2006, Nucleic Acids Res..

[79]  S. L. Mayo,et al.  Computational protein design. , 1999, Structure.

[80]  Simulated evolution of emergent chiral structures in polyalanine. , 2004, Journal of the American Chemical Society.

[81]  B. Imperiali,et al.  Design of a discretely folded mini-protein motif with predominantly β-structure , 2001, Nature Structural Biology.

[82]  P. Balaram,et al.  De novo design of a five-stranded β-sheet anchoring a metal-ion binding site , 2001 .

[83]  Johan Desmet,et al.  The dead-end elimination theorem and its use in protein side-chain positioning , 1992, Nature.

[84]  S. Durani,et al.  A double catgrip mixed L and D mini protein only 20 residues long. , 2007, Bioorganic & medicinal chemistry.

[85]  S. Durani,et al.  Mechanism-based protein design: attempted "nucleation-condensation" approach to a possible minimal helix-bundle protein. , 2003, Biopolymers.

[86]  Marc De Maeyer,et al.  The Dead-End Elimination Theorem: , 2000 .

[87]  D L Weaver,et al.  De novo design and structural characterization of an alpha-helical hairpin peptide: a model system for the study of protein folding intermediates. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[88]  B. Wallace,et al.  The gramicidin pore: crystal structure of a cesium complex. , 1988, Science.

[89]  Homme W Hellinga,et al.  An empirical model for electrostatic interactions in proteins incorporating multiple geometry‐dependent dielectric constants , 2003, Proteins.

[90]  S L Mayo,et al.  De novo protein design: towards fully automated sequence selection. , 1997, Journal of molecular biology.

[91]  J Moult,et al.  Genetic algorithms for protein structure prediction. , 1996, Current opinion in structural biology.

[92]  S. Gellman,et al.  Rules for Antiparallel β-Sheet Design: d-Pro-Gly Is Superior to l-Asn-Gly for β-Hairpin Nucleation1 , 1998 .

[93]  G. Cowie,et al.  Biochemical indicators of diagenetic alteration in natural organic matter mixtures , 1994, Nature.

[94]  R. MacKinnon,et al.  Glycine as a D-amino acid surrogate in the K(+)-selectivity filter. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[95]  L. Miercke,et al.  Structure at 2.5 A of a designed peptide that maintains solubility of membrane proteins. , 1993, Science.

[96]  L. Looger,et al.  Computational design of receptor and sensor proteins with novel functions , 2003, Nature.

[97]  M. Struthers,et al.  Design and NMR analyses of compact, independently folded BBA motifs. , 1998, Folding & design.

[98]  L L Looger,et al.  Generalized dead-end elimination algorithms make large-scale protein side-chain structure prediction tractable: implications for protein design and structural genomics. , 2001, Journal of molecular biology.

[99]  W. DeGrado,et al.  Analysis and design of three-stranded coiled coils and three-helix bundles. , 1998, Folding & design.

[100]  S. L. Mayo,et al.  DREIDING: A generic force field for molecular simulations , 1990 .

[101]  Sara M. Butterfield,et al.  Minimalist Protein Design: A β-Hairpin Peptide That Binds ssDNA , 2005 .

[102]  S L Mayo,et al.  Pairwise calculation of protein solvent-accessible surface areas. , 1998, Folding & design.

[103]  A. Leach,et al.  Ligand docking to proteins with discrete side-chain flexibility. , 1994, Journal of molecular biology.

[104]  S. Durani,et al.  A mixed-α,β miniprotein stereochemically reprogrammed to high-binding affinity for acetylcholine , 2007 .

[105]  D Eisenberg,et al.  Crystal structure of a synthetic triple-stranded alpha-helical bundle. , 1993, Science.

[106]  M. Ghadiri,et al.  Artificial transmembrane ion channels from self-assembling peptide nanotubes , 1994, Nature.

[107]  J. Apostolakis,et al.  Evaluation of a fast implicit solvent model for molecular dynamics simulations , 2002, Proteins.

[108]  Dead-End Based Modeling Tools to Explore the Sequence Space That Is Compatible with a Given Scaffold , 1997, Journal of protein chemistry.

[109]  O. Schueler‐Furman,et al.  Progress in Modeling of Protein Structures and Interactions , 2005, Science.

[110]  I Lasters,et al.  Enhanced dead-end elimination in the search for the global minimum energy conformation of a collection of protein side chains. , 1995, Protein engineering.

[111]  M. Searle,et al.  Structure, folding, and energetics of cooperative interactions between the beta-strands of a de novo sesigned three-stranded antiparallel beta-sheet peptide , 2000 .

[112]  I. Lasters,et al.  Fast and accurate side‐chain topology and energy refinement (FASTER) as a new method for protein structure optimization , 2002, Proteins.

[113]  Roland L. Dunbrack,et al.  Bayesian statistical analysis of protein side‐chain rotamer preferences , 1997, Protein science : a publication of the Protein Society.

[114]  D. Baker,et al.  A large scale test of computational protein design: folding and stability of nine completely redesigned globular proteins. , 2003, Journal of molecular biology.

[115]  R. Hodges,et al.  Defining the minimum size of a hydrophobic cluster in two‐stranded α‐helical coiled‐coils: Effects on protein stability , 2004, Protein science : a publication of the Protein Society.

[116]  B. Wallace,et al.  Recent Advances in the High Resolution Structures of Bacterial Channels: Gramicidin A. , 1998, Journal of structural biology.

[117]  S. L. Mayo,et al.  Probing the role of packing specificity in protein design. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[118]  S. L. Mayo,et al.  Protein design automation , 1996, Protein science : a publication of the Protein Society.

[119]  S. Durani,et al.  A small peptide stereochemically customized as a globular fold with a molecular cleft. , 2005, Chemical communications.