scholarly journals Expanding the space of protein geometries by computational design of de novo fold families

Science ◽  
2020 ◽  
Vol 369 (6507) ◽  
pp. 1132-1136
Author(s):  
Xingjie Pan ◽  
Michael C. Thompson ◽  
Yang Zhang ◽  
Lin Liu ◽  
James S. Fraser ◽  
...  
Keyword(s):  
De Novo ◽  
Design Method ◽  
Computational Design ◽  
Structural Elements ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Structure Space ◽  
Naturally Occurring

Naturally occurring proteins vary the precise geometries of structural elements to create distinct shapes optimal for function. We present a computational design method, loop-helix-loop unit combinatorial sampling (LUCS), that mimics nature’s ability to create families of proteins with the same overall fold but precisely tunable geometries. Through near-exhaustive sampling of loop-helix-loop elements, LUCS generates highly diverse geometries encompassing those found in nature but also surpassing known structure space. Biophysical characterization showed that 17 (38%) of 45 tested LUCS designs encompassing two different structural topologies were well folded, including 16 with designed non-native geometries. Four experimentally solved structures closely matched the designs. LUCS greatly expands the designable structure space and offers a new paradigm for designing proteins with tunable geometries that may be customizable for novel functions.

scholarly journals Expanding the space of protein geometries by computational design of de novo fold families

2020 ◽  
Author(s):  
Xingjie Pan ◽  
Michael Thompson ◽  
Yang Zhang ◽  
Lin Liu ◽  
James S. Fraser ◽  
...  
Keyword(s):  
De Novo ◽  
Design Method ◽  
Computational Design ◽  
Computational Method ◽  
Structural Elements ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Structure Space ◽  
Naturally Occurring ◽  
Designer Proteins

AbstractNaturally occurring proteins use a limited set of fold topologies, but vary the precise geometries of structural elements to create distinct shapes optimal for function. Here we present a computational design method termed LUCS that mimics nature’s ability to create families of proteins with the same overall fold but precisely tunable geometries. Through near-exhaustive sampling of loop-helix-loop elements, LUCS generates highly diverse geometries encompassing those found in nature but also surpassing known structure space. Biophysical characterization shows that 17 (38%) out of 45 tested LUCS designs were well folded, including 16 with designed non-native geometries. Four experimentally solved structures closely match the designs. LUCS greatly expands the designable structure space and provides a new paradigm for designing proteins with tunable geometries customizable for novel functions.One Sentence SummaryA computational method to systematically sample loop-helix-loop geometries expands the structure space of designer proteins.

scholarly journals Computational design of closely related proteins that adopt two well-defined but structurally divergent folds

2020 ◽  
Vol 117 (13) ◽  
pp. 7208-7215 ◽  
Author(s):  
Kathy Y. Wei ◽  
Danai Moschidi ◽  
Matthew J. Bick ◽  
Santrupti Nerli ◽  
Andrew C. McShan ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Conformational Transition ◽  
Protein Structures ◽  
Computational Design ◽  
Spectroscopic Characterization ◽  
De Novo Design ◽  
Viral Fusion ◽  
Naturally Occurring ◽  
Related Proteins

The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used for de novo design of proteins that fold to a single state with a deep free-energy minimum [P.-S. Huang, S. E. Boyken, D. Baker, Nature 537, 320–327 (2016)], and to reengineer natural proteins to alter their dynamics [J. A. Davey, A. M. Damry, N. K. Goto, R. A. Chica, Nat. Chem. Biol. 13, 1280–1285 (2017)] or fold [P. A. Alexander, Y. He, Y. Chen, J. Orban, P. N. Bryan, Proc. Natl. Acad. Sci. U.S.A. 106, 21149–21154 (2009)], the de novo design of closely related sequences which adopt well-defined but structurally divergent structures remains an outstanding challenge. We designed closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations—one short (∼66 Å height) and the other long (∼100 Å height)—reminiscent of the conformational transition of viral fusion proteins. Crystallographic and NMR spectroscopic characterization shows that both the short- and long-state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large-scale conformational switches between structurally divergent forms.

scholarly journals De novo design of transmembrane β-barrels

2020 ◽  
Author(s):  
Anastassia A. Vorobieva ◽  
Paul White ◽  
Binyong Liang ◽  
Jim E Horne ◽  
Asim K. Bera ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Single Molecule ◽  
First Principles ◽  
Lipid Membranes ◽  
De Novo ◽  
Computational Design ◽  
Protein Sequencing ◽  
Naturally Occurring ◽  
Transmembrane Pores ◽  
Almost All

AbstractThe ability of naturally occurring transmembrane β-barrel proteins (TMBs) to spontaneously insert into lipid bilayers and form stable transmembrane pores is a remarkable feat of protein evolution and has been exploited in biotechnology for applications ranging from single molecule DNA and protein sequencing to biomimetic filtration membranes. Because it has not been possible to design TMBs from first principles, these efforts have relied on re-engineering of naturally occurring TMBs that generally have a biological function very different from that desired. Here we leverage the power of de novo computational design coupled with a “hypothesis, design and test” approach to determine principles underlying TMB structure and folding, and find that, unlike almost all other classes of protein, locally destabilizing sequences in both the β-turns and β-strands facilitate TMB expression and global folding by modulating the kinetics of folding and the competition between soluble misfolding and proper folding into the lipid bilayer. We use these principles to design new eight stranded TMBs with sequences unrelated to any known TMB and show that they insert and fold into detergent micelles and synthetic lipid membranes. The designed proteins fold more rapidly and reversibly in lipid membranes than the TMB domain of the model native protein OmpA, and high resolution NMR and X-ray crystal structures of one of the designs are very close to the computational model. The ability to design TMBs from first principles opens the door to custom design of TMBs for biotechnology and demonstrates the value of de novo design to investigate basic protein folding problems that are otherwise hidden by evolutionary history.One sentence summarySuccess in de novo design of transmembrane β-barrels reveals geometric and sequence constraints on the fold and paves the way to design of custom pores for sequencing and other single-molecule analytical applications.

scholarly journals A generative algorithm for de novo design of proteins with diverse pocket structures

2020 ◽  
Author(s):  
Benjamin Basanta ◽  
Matthew J Bick ◽  
Asim K Bera ◽  
Christoffer Norn ◽  
Cameron M Chow ◽  
...  
Keyword(s):  
Small Molecule ◽  
Large Scale ◽  
De Novo ◽  
Experimental Testing ◽  
Biophysical Characterization ◽  
Synthetic Genes ◽  
Precise Control ◽  
Yeast Cell Surface ◽  
Naturally Occurring ◽  
Genes Encoding

AbstractTo create new enzymes and biosensors from scratch, precise control over the structure of small molecule binding sites is of paramount importance, but systematically designing arbitrary protein pocket shapes and sizes remains an outstanding challenge. Using the NTF2-like structural superfamily as a model system, we developed a generative algorithm for creating a virtually unlimited number of de novo proteins supporting diverse pocket structures. The generative algorithm was tested and refined through feedback from two rounds of large scale experimental testing, involving in total, the assembly of synthetic genes encoding 7896 generated designs and assessment of their stability on the yeast cell surface, detailed biophysical characterization of 64 designs, and crystal structures of 5 designs. The refined algorithm generates proteins that remain folded at high temperatures and exhibit more pocket diversity than naturally occurring NTF2-like proteins. We expect this approach to transform the design of small molecule sensors and enzymes by enabling the creation of binding and active site geometries much more optimal for specific design challenges than is accessible by repurposing the limited number of naturally occurring NTF2-like proteins.

scholarly journals An enumerative algorithm for de novo design of proteins with diverse pocket structures

2020 ◽  
Vol 117 (36) ◽  
pp. 22135-22145 ◽  
Author(s):  
Benjamin Basanta ◽  
Matthew J. Bick ◽  
Asim K. Bera ◽  
Christoffer Norn ◽  
Cameron M. Chow ◽  
...  
Keyword(s):  
Small Molecule ◽  
Large Scale ◽  
De Novo ◽  
Experimental Testing ◽  
Biophysical Characterization ◽  
Precise Control ◽  
Yeast Cell Surface ◽  
Naturally Occurring ◽  
Genes Encoding ◽  
Enumerative Algorithm

To create new enzymes and biosensors from scratch, precise control over the structure of small-molecule binding sites is of paramount importance, but systematically designing arbitrary protein pocket shapes and sizes remains an outstanding challenge. Using the NTF2-like structural superfamily as a model system, we developed an enumerative algorithm for creating a virtually unlimited number of de novo proteins supporting diverse pocket structures. The enumerative algorithm was tested and refined through feedback from two rounds of large-scale experimental testing, involving in total the assembly of synthetic genes encoding 7,896 designs and assessment of their stability on yeast cell surface, detailed biophysical characterization of 64 designs, and crystal structures of 5 designs. The refined algorithm generates proteins that remain folded at high temperatures and exhibit more pocket diversity than naturally occurring NTF2-like proteins. We expect this approach to transform the design of small-molecule sensors and enzymes by enabling the creation of binding and active site geometries much more optimal for specific design challenges than is accessible by repurposing the limited number of naturally occurring NTF2-like proteins.

scholarly journals Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds

2019 ◽  
Author(s):  
Kathy Y. Wei ◽  
Danai Moschidi ◽  
Matthew J. Bick ◽  
Santrupti Nerli ◽  
Andrew C. McShan ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Conformational Transition ◽  
Protein Structures ◽  
Computational Design ◽  
Spectroscopic Characterization ◽  
De Novo Design ◽  
Viral Fusion ◽  
Naturally Occurring ◽  
Viral Fusion Proteins

AbstractThe plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used to de novo design proteins that fold to a single state with a deep free energy minima (Huang et al., 2016), and to reengineer natural proteins to alter their dynamics (Davey et al., 2017) or fold (Alexander et al., 2009), the de novo design of closely related sequences which adopt well-defined, but structurally divergent structures remains an outstanding challenge. Here, we design closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations -- one short (∼66 Å height) and the other long (∼100 Å height) -- reminiscent of the conformational transition of viral fusion proteins (Ivanovic et al., 2013; Podbilewicz, 2014; Skehel and Wiley, 2000). Crystallographic and NMR spectroscopic characterization show that both the short and long state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large scale conformational switches between structurally divergent forms.

A Framework for Component Layout and Geometry Design of Mechanical Systems: Configuration Network and its Viewing Control

1995 ◽  
Author(s):  
Kikuo Fujita ◽  
Shinsuke Akagi
Keyword(s):  
Design Method ◽  
Mechanical Systems ◽  
Optimization Procedure ◽  
Computational Design ◽  
Object Oriented Programming ◽  
Design System ◽  
Air Conditioner ◽  
Programming Technique ◽  
Geometry Design ◽  
Component Layout

Abstract A Framework of computational design method and model is proposed for layout and geometry design of complicated mechanical systems, which is named “configuration network and its viewing control”. In the method, a design object is represented with a set of declarative relationships among various elements of a system, that is, configurations, which is gradually extended from schematic structure to exact layout and geometry through design process. Since a whole of such configurations forms a too complicated network to compute all together, how to view subparts is controlled based on levels of granularity and width of scope range. Such a configuration network is made to grow and refined through embodying geometry and layout corresponding to a focused subpart with a numerical optimization procedure. The framework has also an ability to flexibly integrate with engineering analysis. Moreover, a design system is implemented with an object-oriented programming technique, and it is applied to a design problem of air conditioner units in order to show the validity and effectiveness of the framework.

Computational Design for Digitally Fabricated 3D Inductive Power Transfer Coils

2022 ◽  
pp. 1-28
Author(s):  
Jun Xu ◽  
Eugeni L. Doubrovski ◽  
Jo Geraedts ◽  
Yu Song
Keyword(s):  
Design Method ◽  
Computational Design ◽  
Future Research ◽  
Receiver Coil ◽  
Power Transfer ◽  
Coil Design ◽  
Optimal Position ◽  
Inductive Power Transfer ◽  
Transmitter Coil ◽  
Inductive Power

Abstract The geometric shapes and the relative position of coils influence the performance of a three-dimensional (3D) inductive power transfer system. In this paper, we propose a coil design method for specifying the positions and the shapes of a pair of coils to transmit the desired power in 3D. Given region of interests (ROIs) for designing the transmitter and the receiver coils on two surfaces, the transmitter coil is generated around the center of its ROI first. The center of the receiver coil is estimated as a random seed position in the corresponding 3D surface. At this position, we use the heatmap method with electromagnetic constraints to iteratively extend the coil until the desired power can be transferred via the set of coils. In each step, the shape of the extension, i.e. a new turn of the receiver coil, is found as a spiral curve based on the convex hulls of adjacent turns in the 2D projection plane along their normal direction. Then, the optimal position of the receiver coil is found by maximizing the efficiency of the system. In the next step, the position and the shape of the transmitter coil are optimized based on the fixed receiver coil using the same method. This zig-zag optimization process iterates until an optimum is reached. Simulations and experiments with digitally fabricated prototypes were conducted and the effectiveness of the proposed 3D coil design method was verified. Possible future research directions are highlighted well.

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 Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

2021 ◽  
Author(s):  
Lionel B. Ivashkiv ◽  
Chao Yang ◽  
Mahesh Bachu ◽  
Caroline Brauner ◽  
Ruoxi Yuan ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Immune Cells ◽  
De Novo ◽  
Inflammatory Diseases ◽  
Human Monocytes ◽  
Cytokine Storm ◽  
New Paradigm ◽  
Inflammatory Genes ◽  
Synergistic Activation ◽  
Fibrotic Diseases

Abstract CXCL4 regulates responses of immune cells to endosomal TLRs and has been implicated in the pathogenesis of inflammatory and fibrotic diseases. However, mechanisms by which CXCL4 modulates TLR responses, and its functions in monocytes/macrophages, are still unclear. Here we report that CXCL4 changes the profile of the TLR8 response in human monocytes by selectively and dramatically amplifying inflammatory gene transcription and IL-1β production while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKKε and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for a second signal. CXCL4 strongly induced chromatin remodeling in a cooperative and synergistic manner with TLR8 signaling, inducing de novo enhancers associated with inflammatory genes. These findings identify signaling and epigenomic mechanisms that underly synergistic activation of inflammatory genes by CXCL4 and TLR8, provide a new paradigm for modulation of TLR responses that is relevant for cytokine storm, and suggest targeting the TBK1/IKKε-IRF5 axis may be beneficial in inflammatory diseases.

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