Skip to main content
SpringerLink
Log in

Creating novel protein scripts beyond natural alphabets

  • Research Paper
  • Published:
Systems and Synthetic Biology

Abstract

Natural proteins are concatenated amino acids with definite handedness or chirality, with their spatial orientation being preferentially left handed or L-chiral. This paper discusses the biophysics of stereo-chemical perturbation to proteins using D-(α) amino acid and its utility as an additional design alphabet while scripting novel protein structures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Allen BD, Mayo SL (2010) An efficient algorithm for multistate protein design based on FASTER. J Comput Chem 31(5):904–916

    PubMed  CAS  Google Scholar 

  • Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181(96):223–230

    Article  PubMed  CAS  Google Scholar 

  • Anfinsen CB, Scheraga HA (1975) Experimental and theoretical aspects of protein folding. Adv Protein Chem 29:205–300

    Article  PubMed  CAS  Google Scholar 

  • Avbelj F, Baldwin RL (2002) Role of backbone solvation in determining thermodynamic beta propensities of the amino acids. Proc Natl Acad Sci USA 99(3):1309–1313

    Article  PubMed  CAS  Google Scholar 

  • Avbelj F, Moult J (1995) Role of electrostatic screening in determining protein main chain conformational preferences. Biochemistry 34(3):755–764

    Article  PubMed  CAS  Google Scholar 

  • Baker D (2010) An exciting but challenging road ahead for computational enzyme design. Protein Sci 19(10):1817–1819

    Article  PubMed  CAS  Google Scholar 

  • Baldwin RL (2007) Energetics of protein folding. J Mol Biol 371(2):283–301

    Article  PubMed  CAS  Google Scholar 

  • Billmeyer FW (1984) Textbook of polymer science, 3rd edn. Wiley Interscience, New York

    Google Scholar 

  • Billot-Klein D, Legrand R, Schoot B, Van Heijenoort J, Gutmann L (1997) Peptidoglycan structure of Lactobacillus casei, a species highly resistant to glycopeptide antibiotics. J Bacteriol 179(19):6208–6212

    PubMed  CAS  Google Scholar 

  • Bobde V, Beri S, Durani S (1993) Stable type II’ reverse turn-310 helix conformation of Boc-D-Glu-Ala-Gly-Lys-Ala-Leu-OMe in apolar solvents. Tetrahedron 49(24):5397–5406

    Article  CAS  Google Scholar 

  • Brant DA, Flory PJ (1965a) The configuration of random polypeptide chains. i. Experimental results. J Am Chem Soc 87(13):2788–2791. doi:10.1021/ja01091a002

    Article  CAS  Google Scholar 

  • Brant DA, Flory PJ (1965b) The configuration of random polypeptide chains. II. Theory. J Am Chem Soc 87(13):2791–2800. doi:10.1021/ja01091a003

    Article  CAS  Google Scholar 

  • Brueckner H, Becker D, Luepke M (1993) Chirality of amino acids of microorganisms used in food biotechnology. Chirality 5(5):385–392

    Article  CAS  Google Scholar 

  • Chothia C (1992) Proteins. One thousand families for the molecular biologist. Nature 357(6379):543–544

    Article  PubMed  CAS  Google Scholar 

  • Chou PY, Fasman GD (1974) Prediction of protein conformation. Biochemistry 13(2):222–245

    Article  PubMed  CAS  Google Scholar 

  • Cooper S, Khatib F, Treuille A, Barbero J, Lee J, Beenen M, Leaver-Fay A, Baker D, Popovic Z, Players F (2010) Predicting protein structures with a multiplayer online game. Nature 466(7307):756–760

    Article  PubMed  CAS  Google Scholar 

  • Creamer TP, Rose GD (1992) Side-chain entropy opposes alpha-helix formation but rationalizes experimentally determined helix-forming propensities. Proc Natl Acad Sci USA 89(13):5937–5941

    Article  PubMed  CAS  Google Scholar 

  • Daura X, van Gunsteren WF, Mark AE (1999) Folding–unfolding thermodynamics of a β-heptapeptide from equilibrium simulations. Proteins: structure, function, and bioinformatics 34:269–280. doi:10.1002/(sici)1097-0134(19990215)34:3<269:aid-prot1>3.0.co;2-3

    Article  CAS  Google Scholar 

  • Daura X, Gademann K, Schafer H, Jaun B, Seebach D, van Gunsteren WF (2001) The beta-peptide hairpin in solution: conformational study of a beta-hexapeptide in methanol by NMR spectroscopy and MD simulation. J Am Chem Soc 123(10):2393–2404

    Article  PubMed  CAS  Google Scholar 

  • Dhanasekaran M, Fabiola F, Pattabhi V, Durani S (1999) A rationally designed turn-helix peptide. J Am Chem Soc 121(23):5575–5576. doi:10.1021/ja984237v

    Article  CAS  Google Scholar 

  • Donohue J (1953) hydrogen bonded helical configurations of the polypeptide chain. Proc Natl Acad Sci USA 39(6):470–478

    Article  PubMed  CAS  Google Scholar 

  • Durani S (2008) Protein design with l- and d-alpha-amino acid structures as the alphabet. Acc Chem Res 41(10):1301–1308

    Article  PubMed  CAS  Google Scholar 

  • Eisenberg D (2003) The discovery of the alpha-helix and beta-sheet, the principal structural features of proteins. Proc Natl Acad Sci USA 100(20):11207–11210

    Article  PubMed  CAS  Google Scholar 

  • Fabiola F, Pattabhi V, Rawale S, Raju EB, Durani S (1997) Configurationally guided peptide conformational motifs: crystal structure of a l[small alpha]d[small beta]l[small beta]d[small alpha] d[small beta]l[small alpha] type hexapeptide fold. Chem Commun 15:1379–1380

    Article  Google Scholar 

  • Fitzkee NC, Rose GD (2004) Reassessing random-coil statistics in unfolded proteins. Proc Natl Acad Sci USA 101(34):12497–12502

    Article  PubMed  CAS  Google Scholar 

  • Flory PJ (1969) Statistical Mechanics of Chain Molecules. Interscience, New York

    Google Scholar 

  • Ghadiri MR, Granja JR, Buehler LK (1994) Artificial transmembrane ion channels from self-assembling peptide nanotubes. Nature 369(6478):301–304

    Article  PubMed  CAS  Google Scholar 

  • Golovine S, Hecht SM, Dedkova L (2004) Methods of protein synthesis incorporating D-amino acids using modified ribosomes with 23S rRNA gene mutations. WO Patent 2003-US33108; 2004035757

  • Jack RW, Jung G (1998) Natural peptides with antimicrobial activity. Chimia 52(1–2):48–55

    CAS  Google Scholar 

  • Joshi S, Rana S, Wangikar P, Durani S (2006) Computational design of proteins stereochemically optimized in size, stability, and folding speed. Biopolymers 83(2):122–134

    Article  PubMed  CAS  Google Scholar 

  • Kohn JE, Millett IS, Jacob J, Zagrovic B, Dillon TM, Cingel N, Dothager RS, Seifert S, Thiyagarajan P, Sosnick TR, Hasan MZ, Pande VS, Ruczinski I, Doniach S, Plaxco KW (2004) Random-coil behavior and the dimensions of chemically unfolded proteins. Proc Natl Acad Sci USA 101(34):12491–12496

    Article  PubMed  CAS  Google Scholar 

  • Korendovych IV, Senes A, Kim YH, Lear JD, Fry HC, Therien MJ, Blasie JK, Walker FA, Degrado WF (2010) De novo design and molecular assembly of a transmembrane diporphyrin-binding protein complex. J Am Chem Soc 132(44):15516–15518

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Ramakrishnan V, Ranbhor R, Patel K, Durani S (2009) Homochiral stereochemistry: the missing link of structure to energetics in protein folding. J Phys Chem B 113(51):16435–16442

    Article  PubMed  CAS  Google Scholar 

  • Leach AR (2001) Molecular modelling: principles and applications, 2nd edn. Prentice Hall, England

    Google Scholar 

  • Leach SJ, Nemethy G, Scheraga HA (1966) Computation of the sterically allowed conformations of peptides. Biopolymers 4(4):369–407

    Article  PubMed  CAS  Google Scholar 

  • Marahiel MA (2009) Working outside the protein-synthesis rules: insights into non-ribosomal peptide synthesis. J Pept Sci 15(12):799–807

    Article  PubMed  CAS  Google Scholar 

  • Marahiel MA, Essen LO (2009) Chapter 13. Nonribosomal peptide synthetases mechanistic and structural aspects of essential domains. Methods Enzymol 458:337–351

    Article  PubMed  CAS  Google Scholar 

  • Martinez del Pozo A, Pospischil MA, Ueno H, Manning JM, Tanizawa K, Nishimura K, Soda K, Ringe D, Stoddard B, Petsko GA (1989) Effects of d-serine on bacterial d-amino acid transaminase: accumulation of an intermediate and inactivation of the enzyme. Biochemistry 28(22):8798–8803

    Article  PubMed  CAS  Google Scholar 

  • Miller WG, Brant DA, Flory PJ (1967) Random coil configurations of polypeptide copolymers. J Mol Biol 23(1):67–80

    Article  CAS  Google Scholar 

  • Mohanraja K, Dhanasekaran M, Kundu B, Durani S (2003) Mechanism-based protein design: attempted “nucleation-condensation” approach to a possible minimal helix-bundle protein. Biopolymers 70(3):355–363

    Article  PubMed  CAS  Google Scholar 

  • Nanda V, DeGrado WF (2006) Computational design of heterochiral peptides against a helical target. J Am Chem Soc 128(3):809–816

    Article  PubMed  CAS  Google Scholar 

  • Patel K, Srivastava KR, Durani S (2010) Zinc-finger hydrolase: Computational selection of a linker and a sequence towards metal activation with a synthetic alphabetabeta protein. Bioorg Med Chem 2010:27

    Google Scholar 

  • Pauling L, Corey RB (1950) Two hydrogen-bonded spiral configurations of the polypeptide chain. J Am Chem Soc 72(11):5349. doi:10.1021/ja01167a545

    Article  CAS  Google Scholar 

  • Pauling L, Corey RB, Branson HR (1951) The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. Proc Natl Acad Sci USA 37(4):205–211

    Article  PubMed  CAS  Google Scholar 

  • Presta LG, Rose GD (1988) Helix signals in proteins. Science 240(4859):1632–1641

    Article  PubMed  CAS  Google Scholar 

  • Ramachandran GN, Sasisekharan V (1968) Conformation of polypeptides and proteins. Adv Protein Chem 23:283–438

    Article  PubMed  CAS  Google Scholar 

  • Ramachandran GN, Ramakrishnan C, Sasisekharan V (1963) Stereochemistry of polypeptide chain configurations. J Mol Biol 7:95–99

    Article  PubMed  CAS  Google Scholar 

  • Ramakrishnan V, Ranbhor R, Durani S (2005) Simulated folding in polypeptides of diversified molecular tacticity: implications for protein folding and de novo design. Biopolymers 78(2):96–105

    Article  PubMed  CAS  Google Scholar 

  • Ramakrishnan V, Ranbhor R, Kumar A, Durani S (2006) The link between sequence and conformation in protein structures appears to be stereochemically established. J Phys Chem B 110(18):9314–9323

    Article  PubMed  CAS  Google Scholar 

  • Rana S, Kundu B, Durani S (2004) Stereospecific peptide folds. A rationally designed molecular bracelet. Chem Commun (Camb) (21):2462–2463

  • Rana S, Kundu B, Durani S (2005) A small peptide stereochemically customized as a globular fold with a molecular cleft. Chem Commun (Camb) (2):207–209

  • Rana S, Kundu B, Durani S (2007a) A double catgrip mixed l and d mini protein only 20 residues long. Bioorg Med Chem 15(11):3874–3882

    Article  PubMed  CAS  Google Scholar 

  • Rana S, Kundu B, Durani S (2007b) A mixed-alpha, beta miniprotein stereochemically reprogrammed to high-binding affinity for acetylcholine. Biopolymers 87(4):231–243

    Article  PubMed  CAS  Google Scholar 

  • Ranbhor R, Ramakrishnan V, Kumar A, Durani S (2006) The interplay of sequence and stereochemistry in defining conformation in proteins and polypeptides. Biopolymers 83(5):537–545

    Article  PubMed  CAS  Google Scholar 

  • Richardson JS, Richardson DC (1988) Amino acid preferences for specific locations at the ends of alpha helices. Science 240(4859):1648–1652

    Article  PubMed  CAS  Google Scholar 

  • Robinson T (1976) D-Amino acids in higher plants. Life Sci 19(8):1097–1102

    Article  PubMed  CAS  Google Scholar 

  • Rohl CA, Strauss CE, Misura KM, Baker D (2004) Protein structure prediction using Rosetta. Methods Enzymol 383:66–93

    Article  PubMed  CAS  Google Scholar 

  • Rose GD, Gierasch LM, Smith JA (1985) Turns in peptides and proteins. Adv Protein Chem 37:1–109

    Article  PubMed  CAS  Google Scholar 

  • Rose GD, Fleming PJ, Banavar JR, Maritan A (2006) A backbone-based theory of protein folding. Proc Natl Acad Sci USA 103(45):16623–16633

    Article  PubMed  CAS  Google Scholar 

  • Sibanda BL, Thornton JM (1985) Beta-hairpin families in globular proteins. Nature 316(6024):170–174

    Article  PubMed  CAS  Google Scholar 

  • Sibanda BL, Blundell TL, Thornton JM (1989) Conformation of beta-hairpins in protein structures. A systematic classification with applications to modelling by homology, electron density fitting and protein engineering. J Mol Biol 206(4):759–777

    Article  PubMed  CAS  Google Scholar 

  • Struthers MD, Cheng RP, Imperiali B (1996) Design of a monomeric 23-residue polypeptide with defined tertiary structure. Science 271(5247):342–345

    Article  PubMed  CAS  Google Scholar 

  • Szabo G, Urry DW (1979) N-acetyl gramicidin: single-channel properties and implications for channel structure. Science 203(4375):55–57

    Article  PubMed  CAS  Google Scholar 

  • Tanford C (1968) Protein denaturation. Adv Protein Chem 23:121–282

    Article  PubMed  CAS  Google Scholar 

  • Urry DW (1971) The gramicidin A transmembrane channel: a proposed pi(L, D) helix. Proc Natl Acad Sci USA 68(3):672–676

    Article  PubMed  CAS  Google Scholar 

  • van Gunsteren WF, Billeter SR, Hünenberger PH, Krüger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide. Vdf Hochschulverlag AG an der ETH Zürich, Zürich

    Google Scholar 

  • Wallace BA (1998) Recent advances in the high resolution structures of bacterial channels: gramicidin A. J Struct Biol 121(2):123–141

    Article  PubMed  CAS  Google Scholar 

  • Wallace BA (2000) Common structural features in gramicidin and other ion channels. Bioessays 22(3):227–234

    Article  PubMed  CAS  Google Scholar 

  • Watson JD, Milner-White EJ (2002a) 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. J Mol Biol 315(2):183–191

    Article  PubMed  CAS  Google Scholar 

  • Watson JD, Milner-White EJ (2002b) 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. J Mol Biol 315(2):171–182

    Article  PubMed  CAS  Google Scholar 

  • Weaver TM (2000) The pi-helix translates structure into function. Protein Sci 9(1):201–206

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan R RIBOSOME V1.0. http://roselab.jhu.edu/~raj/Manuals/ribosome.html

  • Zhang C, DeLisi C (1998) Estimating the number of protein folds. J Mol Biol 284(5):1301–1305

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Authors thank Prof. Susheel Durani for the core concept of this manuscript. VR thanks IYBA program of Dept of Biotechnology, Govt. of India for funding. The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada

    Anil Kumar

  2. Rajiv Gandhi Centre for Biotechnology, Thiruvanthapuram, Kerala, 695014, India

    Vibin Ramakrishnan

Authors
  1. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vibin Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vibin Ramakrishnan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, A., Ramakrishnan, V. Creating novel protein scripts beyond natural alphabets. Syst Synth Biol 4, 247–256 (2010). https://doi.org/10.1007/s11693-011-9068-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11693-011-9068-5

Keywords

Search

Navigation