scholarly journals Precise assembly of complex beta sheet topologies from de novo designed building blocks

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Indigo Chris King ◽  
James Gleixner ◽  
Lindsey Doyle ◽  
Alexandre Kuzin ◽  
John F Hunt ◽  
...  
Keyword(s):  
De Novo ◽  
Computational Design ◽  
Building Blocks ◽  
Beta Sheets ◽  
Protein Domain ◽  
Beta Sheet ◽  
Design Models ◽  
Natural Protein ◽  
Complex Protein ◽  
Alpha Beta

Design of complex alpha-beta protein topologies poses a challenge because of the large number of alternative packing arrangements. A similar challenge presumably limited the emergence of large and complex protein topologies in evolution. Here, we demonstrate that protein topologies with six and seven-stranded beta sheets can be designed by insertion of one de novo designed beta sheet containing protein into another such that the two beta sheets are merged to form a single extended sheet, followed by amino acid sequence optimization at the newly formed strand-strand, strand-helix, and helix-helix interfaces. Crystal structures of two such designs closely match the computational design models. Searches for similar structures in the SCOP protein domain database yield only weak matches with different beta sheet connectivities. A similar beta sheet fusion mechanism may have contributed to the emergence of complex beta sheets during natural protein evolution.

scholarly journals De novo design of self-assembling helical protein filaments

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 705-709 ◽  
Author(s):  
Hao Shen ◽  
Jorge A. Fallas ◽  
Eric Lynch ◽  
William Sheffler ◽  
Bradley Parry ◽  
...  
Keyword(s):  
De Novo ◽  
Computational Design ◽  
Building Blocks ◽  
Repeat Units ◽  
Self Assembling ◽  
Wide Range ◽  
Helical Protein ◽  
Monomeric Proteins

We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo–electron microscopy structures of six designs are close to the computational design models. The filament building blocks are idealized repeat proteins, and thus the diameter of the filaments can be systematically tuned by varying the number of repeat units. The assembly and disassembly of the filaments can be controlled by engineered anchor and capping units built from monomers lacking one of the interaction surfaces. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials.

scholarly journals Computational design of highly signaling active membrane receptors through de novo solvent-mediated allosteric networks

2021 ◽  
Author(s):  
Michael Chen ◽  
Jason Lai ◽  
Jing Wang ◽  
Kris Conners ◽  
Anna Russell ◽  
...  
Keyword(s):  
De Novo ◽  
Solvent Molecule ◽  
Interaction Network ◽  
Computational Design ◽  
Cooperative Networks ◽  
Membrane Receptors ◽  
Nucleotide Exchange ◽  
Protein Activity ◽  
Complex Protein ◽  
Molecule Interactions

Protein catalysis and allostery require the atomic-level orchestration and motion of residues, ligand, solvent and protein effector molecules, but the ability to design protein activity through precise protein-solvent cooperative interactions has not been demonstrated. Here, we report the design of a dozen novel membrane receptors catalyzing G-protein nucleotide exchange through diverse de novo engineered allosteric pathways mediated by cooperative networks of intra-protein, protein-ligand and solvent molecule interactions. Consistent with the predictions, designed protein activities strongly correlated with the level of solvent-mediated interaction network plasticity at flexible transmembrane helical interfaces. Several designs displayed considerably enhanced thermostability and activity compared to related natural receptors. The most stable and active variant crystallized in an unforeseen signaling active conformation, in excellent agreement with the design models. The allosteric network topologies of the best designs bear limited similarity to those of natural receptors and reveal a space of allosteric interactions larger than previously inferred from natural proteins. The approach should prove useful for engineering proteins with novel complex protein catalytic and signaling activities.

scholarly journals Design of multi-scale protein complexes by hierarchical building block fusion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yang Hsia ◽  
Rubul Mout ◽  
William Sheffler ◽  
Natasha I. Edman ◽  
Ivan Vulovic ◽  
...  
Keyword(s):  
Building Block ◽  
De Novo ◽  
Protein Complexes ◽  
Point Group ◽  
Building Blocks ◽  
X Ray Crystallography ◽  
Wide Range ◽  
Complex Protein ◽  
Microscopy Characterization ◽  
Group Symmetries

AbstractA systematic and robust approach to generating complex protein nanomaterials would have broad utility. We develop a hierarchical approach to designing multi-component protein assemblies from two classes of modular building blocks: designed helical repeat proteins (DHRs) and helical bundle oligomers (HBs). We first rigidly fuse DHRs to HBs to generate a large library of oligomeric building blocks. We then generate assemblies with cyclic, dihedral, and point group symmetries from these building blocks using architecture guided rigid helical fusion with new software named WORMS. X-ray crystallography and cryo-electron microscopy characterization show that the hierarchical design approach can accurately generate a wide range of assemblies, including a 43 nm diameter icosahedral nanocage. The computational methods and building block sets described here provide a very general route to de novo designed protein nanomaterials.

scholarly journals Supramolecular assembly of protein building blocks: from folding to function

2022 ◽  
Vol 9 (1) ◽  
Author(s):  
Nam Hyeong Kim ◽  
Hojae Choi ◽  
Zafar Muhammad Shahzad ◽  
Heesoo Ki ◽  
Jaekyoung Lee ◽  
...  
Keyword(s):  
Self Assembly ◽  
De Novo ◽  
Complex Structure ◽  
Supramolecular Assembly ◽  
Hierarchical Structures ◽  
Computational Design ◽  
Building Blocks ◽  
Biological Phenomena ◽  
Living Things ◽  
Protein Interfaces

AbstractSeveral phenomena occurring throughout the life of living things start and end with proteins. Various proteins form one complex structure to control detailed reactions. In contrast, one protein forms various structures and implements other biological phenomena depending on the situation. The basic principle that forms these hierarchical structures is protein self-assembly. A single building block is sufficient to create homogeneous structures with complex shapes, such as rings, filaments, or containers. These assemblies are widely used in biology as they enable multivalent binding, ultra-sensitive regulation, and compartmentalization. Moreover, with advances in the computational design of protein folding and protein–protein interfaces, considerable progress has recently been made in the de novo design of protein assemblies. Our review presents a description of the components of supramolecular protein assembly and their application in understanding biological phenomena to therapeutics.

scholarly journals Author response: Precise assembly of complex beta sheet topologies from de novo designed building blocks

2015 ◽  
Author(s):  
Indigo Chris King ◽  
James Gleixner ◽  
Lindsey Doyle ◽  
Alexandre Kuzin ◽  
John F Hunt ◽  
...  
Keyword(s):  
De Novo ◽  
Building Blocks ◽  
Author Response ◽  
Beta Sheet

De Novo Synthesis of l-Colitose and l-Rhodinose Building Blocks

2011 ◽  
Vol 77 (2) ◽  
pp. 870-877 ◽  
Author(s):  
Oliviana Calin ◽  
Rajan Pragani ◽  
Peter H. Seeberger
Keyword(s):  
De Novo ◽  
Building Blocks ◽  
De Novo Synthesis

scholarly journals EnTAP: Bringing Faster and Smarter Functional Annotation to Non-Model Eukaryotic Transcriptomes

2018 ◽  
Author(s):  
Alexander J. Hart ◽  
Samuel Ginzburg ◽  
Muyang (Sam) Xu ◽  
Cera R. Fisher ◽  
Nasim Rahmatpour ◽  
...  
Keyword(s):  
Similarity Search ◽  
De Novo ◽  
Gene Annotation ◽  
Enrichment Analysis ◽  
Orthologous Gene ◽  
Protein Domain ◽  
Family Assessment ◽  
Ontology Term ◽  
Protein Coding ◽  
Functional Gene Annotation

ABSTRACTEnTAP (Eukaryotic Non-Model Transcriptome Annotation Pipeline) was designed to improve the accuracy, speed, and flexibility of functional gene annotation for de novo assembled transcriptomes in non-model eukaryotes. This software package addresses the fragmentation and related assembly issues that result in inflated transcript estimates and poor annotation rates, while focusing primarily on protein-coding transcripts. Following filters applied through assessment of true expression and frame selection, open-source tools are leveraged to functionally annotate the translated proteins. Downstream features include fast similarity search across three repositories, protein domain assignment, orthologous gene family assessment, and Gene Ontology term assignment. The final annotation integrates across multiple databases and selects an optimal assignment from a combination of weighted metrics describing similarity search score, taxonomic relationship, and informativeness. Researchers have the option to include additional filters to identify and remove contaminants, identify associated pathways, and prepare the transcripts for enrichment analysis. This fully featured pipeline is easy to install, configure, and runs significantly faster than comparable annotation packages. EnTAP is optimized to generate extensive functional information for the gene space of organisms with limited or poorly characterized genomic resources.

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