scholarly journals Breakthroughs in computational design methods open up new frontiers for de novo protein engineering

2021 ◽  
Vol 34 ◽  
Author(s):  
Ben A Meinen ◽  
Christopher D Bahl
Keyword(s):  
Protein Engineering ◽  
Chemical Reactions ◽  
Protein Design ◽  
De Novo ◽  
Computational Design ◽  
Design Methods ◽  
Computational Protein Design ◽  
The Past ◽  
New Methods ◽  
De Novo Protein Design

Abstract Proteins catalyze the majority of chemical reactions in organisms, and harnessing this power has long been the focus of the protein engineering field. Computational protein design aims to create new proteins and functions in silico, and in doing so, accelerate the process, reduce costs and enable more sophisticated engineering goals to be accomplished. Challenges that very recently seemed impossible are now within reach thanks to several landmark advances in computational protein design methods. Here, we summarize these new methods, with a particular emphasis on de novo protein design advancements occurring within the past 5 years.

scholarly journals De novo design of a homo-trimeric amantadine-binding protein

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jooyoung Park ◽  
Brinda Selvaraj ◽  
Andrew C McShan ◽  
Scott E Boyken ◽  
Kathy Y Wei ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Design ◽  
Metal Ion ◽  
Structural Changes ◽  
De Novo ◽  
Computational Design ◽  
Solution Nmr ◽  
Hydrogen Bond Networks ◽  
De Novo Protein Design ◽  
Design Calculations

The computational design of a symmetric protein homo-oligomer that binds a symmetry-matched small molecule larger than a metal ion has not yet been achieved. We used de novo protein design to create a homo-trimeric protein that binds the C3 symmetric small molecule drug amantadine with each protein monomer making identical interactions with each face of the small molecule. Solution NMR data show that the protein has regular three-fold symmetry and undergoes localized structural changes upon ligand binding. A high-resolution X-ray structure reveals a close overall match to the design model with the exception of water molecules in the amantadine binding site not included in the Rosetta design calculations, and a neutron structure provides experimental validation of the computationally designed hydrogen-bond networks. Exploration of approaches to generate a small molecule inducible homo-trimerization system based on the design highlight challenges that must be overcome to computationally design such systems.

scholarly journals Bottom-up de novo protein design

2021 ◽  
Vol 18 (3) ◽  
pp. 233-233
Author(s):  
Arunima Singh
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Bottom Up ◽  
De Novo Protein Design

Design of Peptide Analogues with Improved Activity Using a Novel de Novo Protein Design Approach

2004 ◽  
Vol 43 (14) ◽  
pp. 3817-3826 ◽  
Author(s):  
J. L. Klepeis ◽  
C. A. Floudas ◽  
D. Morikis ◽  
C. G. Tsokos ◽  
J. D. Lambris
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Design Approach ◽  
De Novo Protein Design ◽  
Peptide Analogues

De Novo protein design: towards fully automated sequence selection 1 1Edited by P. E. Wright

1997 ◽  
Vol 273 (4) ◽  
pp. 789-796 ◽  
Author(s):  
Bassil I Dahiyat ◽  
Catherine A Sarisky ◽  
Stephen L Mayo
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Sequence Selection ◽  
De Novo Protein Design

A prototype computer system for de novo protein design

1994 ◽  
Vol 22 (4) ◽  
pp. 1033-1036
Author(s):  
A. Berry ◽  
S. E. Brenner
Keyword(s):  
Computer System ◽  
Protein Design ◽  
De Novo ◽  
De Novo Protein Design

scholarly journals Protein structure prediction and design in a biologically-realistic implicit membrane

2019 ◽  
Author(s):  
Rebecca F. Alford ◽  
Patrick J. Fleming ◽  
Karen G. Fleming ◽  
Jeffrey J. Gray
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Structure Prediction ◽  
Protein Design ◽  
Structure Prediction ◽  
De Novo ◽  
Computational Design ◽  
Amino Acid Distribution

ABSTRACTProtein design is a powerful tool for elucidating mechanisms of function and engineering new therapeutics and nanotechnologies. While soluble protein design has advanced, membrane protein design remains challenging due to difficulties in modeling the lipid bilayer. In this work, we developed an implicit approach that captures the anisotropic structure, shape of water-filled pores, and nanoscale dimensions of membranes with different lipid compositions. The model improves performance in computational bench-marks against experimental targets including prediction of protein orientations in the bilayer, ΔΔG calculations, native structure dis-crimination, and native sequence recovery. When applied to de novo protein design, this approach designs sequences with an amino acid distribution near the native amino acid distribution in membrane proteins, overcoming a critical flaw in previous membrane models that were prone to generating leucine-rich designs. Further, the proteins designed in the new membrane model exhibit native-like features including interfacial aromatic side chains, hydrophobic lengths compatible with bilayer thickness, and polar pores. Our method advances high-resolution membrane protein structure prediction and design toward tackling key biological questions and engineering challenges.Significance StatementMembrane proteins participate in many life processes including transport, signaling, and catalysis. They constitute over 30% of all proteins and are targets for over 60% of pharmaceuticals. Computational design tools for membrane proteins will transform the interrogation of basic science questions such as membrane protein thermodynamics and the pipeline for engineering new therapeutics and nanotechnologies. Existing tools are either too expensive to compute or rely on manual design strategies. In this work, we developed a fast and accurate method for membrane protein design. The tool is available to the public and will accelerate the experimental design pipeline for membrane proteins.

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