What Has De Novo Protein Design Taught Us About Protein Folding and Biophysics?

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2019 Feb 13

PMID 30746840

Citations 73

Authors

David Baker

Affiliations

Soon will be listed here.

Abstract

Recent progress in de novo protein design has led to an explosion of new protein structures, functions and assemblies. In this essay, I consider how the successes and failures in this new area inform our understanding of the proteins in nature and, more generally, the predictive computational modeling of biological systems.

Citing Articles

Engineering Dehalogenase Enzymes Using Variational Autoencoder-Generated Latent Spaces and Microfluidics.

Kohout P, Vasina M, Majerova M, Novakova V, Damborsky J, Bednar D JACS Au. 2025; 5(2):838-850.

PMID: 40017771 PMC: 11862945. DOI: 10.1021/jacsau.4c01101.

Active site center redesign increases protein stability preserving catalysis in thioredoxin.

Romero M, Garcia Seisdedos H, Ibarra-Molero B Protein Sci. 2024; 31(9):e4417.

PMID: 39287965 PMC: 9601870. DOI: 10.1002/pro.4417.

Development of artificial photosystems based on designed proteins for mechanistic insights into photosynthesis.

Serrano G, Echavarria C, Mejias S Protein Sci. 2024; 33(10):e5164.

PMID: 39276008 PMC: 11400635. DOI: 10.1002/pro.5164.

Computational design of de novo bioenergetic membrane proteins.

Hardy B, Curnow P Biochem Soc Trans. 2024; 52(4):1737-1745.

PMID: 38958574 PMC: 11668274. DOI: 10.1042/BST20231347.

How much metagenome data is needed for protein structure prediction: The advantages of targeted approach from the ecological and evolutionary perspectives.

Yang P, Ning K Imeta. 2024; 1(1):e9.

PMID: 38867727 PMC: 10989767. DOI: 10.1002/imt2.9.

References

Huang P, Boyken S, Baker D . The coming of age of de novo protein design. Nature. 2016; 537(7620):320-7. DOI: 10.1038/nature19946. View

Baker D, Sohl J, Agard D . A protein-folding reaction under kinetic control. Nature. 1992; 356(6366):263-5. DOI: 10.1038/356263a0. View

Chen Z, Boyken S, Jia M, Busch F, Flores-Solis D, Bick M . Programmable design of orthogonal protein heterodimers. Nature. 2018; 565(7737):106-111. PMC: 6537907. DOI: 10.1038/s41586-018-0802-y. View

Bale J, Gonen S, Liu Y, Sheffler W, Ellis D, Thomas C . Accurate design of megadalton-scale two-component icosahedral protein complexes. Science. 2016; 353(6297):389-94. PMC: 5485857. DOI: 10.1126/science.aaf8818. View

Ovchinnikov S, Park H, Varghese N, Huang P, Pavlopoulos G, Kim D . Protein structure determination using metagenome sequence data. Science. 2017; 355(6322):294-298. PMC: 5493203. DOI: 10.1126/science.aah4043. View

Brunette T, Parmeggiani F, Huang P, Bhabha G, Ekiert D, Tsutakawa S . Exploring the repeat protein universe through computational protein design. Nature. 2015; 528(7583):580-4. PMC: 4845728. DOI: 10.1038/nature16162. View

Hosseinzadeh P, Bhardwaj G, Mulligan V, Shortridge M, Craven T, Pardo-Avila F . Comprehensive computational design of ordered peptide macrocycles. Science. 2017; 358(6369):1461-1466. PMC: 5860875. DOI: 10.1126/science.aap7577. View

Riddle D, Santiago J, Doshi N, Grantcharova V, Yi Q, Baker D . Functional rapidly folding proteins from simplified amino acid sequences. Nat Struct Biol. 1997; 4(10):805-9. DOI: 10.1038/nsb1097-805. View

Dou J, Vorobieva A, Sheffler W, Doyle L, Park H, Bick M . De novo design of a fluorescence-activating β-barrel. Nature. 2018; 561(7724):485-491. PMC: 6275156. DOI: 10.1038/s41586-018-0509-0. View

10.

Marcos E, Basanta B, Chidyausiku T, Tang Y, Oberdorfer G, Liu G . Principles for designing proteins with cavities formed by curved β sheets. Science. 2017; 355(6321):201-206. PMC: 5588894. DOI: 10.1126/science.aah7389. View

11.

Boyken S, Chen Z, Groves B, Langan R, Oberdorfer G, Ford A . De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity. Science. 2016; 352(6286):680-7. PMC: 5497568. DOI: 10.1126/science.aad8865. View

12.

Baker D . A surprising simplicity to protein folding. Nature. 2000; 405(6782):39-42. DOI: 10.1038/35011000. View

13.

Koga N, Tatsumi-Koga R, Liu G, Xiao R, Acton T, Montelione G . Principles for designing ideal protein structures. Nature. 2012; 491(7423):222-7. PMC: 3705962. DOI: 10.1038/nature11600. View

14.

Kim D, Gu H, Baker D . The sequences of small proteins are not extensively optimized for rapid folding by natural selection. Proc Natl Acad Sci U S A. 1998; 95(9):4982-6. PMC: 20199. DOI: 10.1073/pnas.95.9.4982. View

15.

Kuhlman B, Dantas G, Ireton G, Varani G, Stoddard B, Baker D . Design of a novel globular protein fold with atomic-level accuracy. Science. 2003; 302(5649):1364-8. DOI: 10.1126/science.1089427. View

16.

Lu P, Min D, DiMaio F, Wei K, Vahey M, Boyken S . Accurate computational design of multipass transmembrane proteins. Science. 2018; 359(6379):1042-1046. PMC: 7328376. DOI: 10.1126/science.aaq1739. View

17.

Plaxco K, Simons K, Baker D . Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol. 1998; 277(4):985-94. DOI: 10.1006/jmbi.1998.1645. View

18.

Simons K, Kooperberg C, Huang E, Baker D . Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and Bayesian scoring functions. J Mol Biol. 1997; 268(1):209-25. DOI: 10.1006/jmbi.1997.0959. View