Featured
-
-
News & Views |
Machine learning trims the peptide drug design process to a sweet spot
Drugs that target peptide hormone receptors are of great interest in the treatment of type 2 diabetes. In spite of limited data and vast design spaces, a bespoke computational pipeline has designed peptides that target two receptors with high potency.
- Chloe E. Markey
- & Daniel Reker
-
Article
| Open AccessMachine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency
Engineering new ligands that specifically target multiple G protein-coupled receptors with desired activity profiles requires time-consuming and expensive cycles of design-make-test-analyse work. Now it has been shown that limited experimental data can be used to train sophisticated machine learning models to accurately predict the activity of previously uncharacterized peptide ligand variants.
- Anna M. Puszkarska
- , Bruck Taddese
- & Lucy J. Colwell
-
Article
| Open AccessAsymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility
The biomolecular principles underlying the formation of multiphasic condensates have been difficult to elucidate owing to a paucity of tools, especially within living cells. In this work synthetic orthogonal protein scaffolds alongside molecular simulations are used to highlight how the oligomerization of disordered proteins can asymmetrically drive miscibility–immiscibility transitions.
- Ushnish Rana
- , Ke Xu
- & Clifford P. Brangwynne
-
News & Views |
Discovering cryptic natural products by substrate manipulation
Cryptic halogenation reactions result in natural products with diverse structural motifs and bioactivities. However, these halogenated species are difficult to detect with current analytical methods because the final products are often not halogenated. An approach to identify products of cryptic halogenation using halide depletion has now been discovered, opening up space for more effective natural product discovery.
- Ludek Sehnal
- , Libera Lo Presti
- & Nadine Ziemert
-
News & Views |
Using symmetry to drive new protein assemblies
Recent improvements in de novo protein design are likely to support a broad range of applications, but larger complexes will be easier to create if a building block approach is adopted. Now protein filaments with tunable geometry can be made using assemblies that have both cyclic and superhelical symmetries aligned along the same axis.
- Jeremy R. H. Tame
-
Article
| Open AccessEnabling late-stage drug diversification by high-throughput experimentation with geometric deep learning
Late-stage functionalization of complex drug molecules is challenging. To address this problem, a discovery platform based on geometric deep learning and high-throughput experimentation was developed. The computational model predicts binary reaction outcome, reaction yield and regioselectivity with low error margins, enabling the functionalization of complex molecules without de novo synthesis.
- David F. Nippa
- , Kenneth Atz
- & Gisbert Schneider
-
Article
| Open AccessDesign of allosteric sites into rotary motor V1-ATPase by restoring lost function of pseudo-active sites
Allostery produces concerted functions of protein complexes by orchestrating the cooperative work between the constituent subunits. By restoring functions of pseudo-active sites that have been lost through evolution, allosteric sites have now been designed into a rotary molecular motor, V1-ATPase, resulting in its rotation being boosted allosterically.
- Takahiro Kosugi
- , Tatsuya Iida
- & Nobuyasu Koga
-
Article |
The dynamics of agonist-β2-adrenergic receptor activation induced by binding of GDP-bound Gs protein
Contrary to agonist binding being the sole driver for β2-adrenergic receptor (β2AR) activation, molecular metadynamics simulations now reveal a distinct activation mechanism. Coupling β2AR with its cognate Gs protein induces considerable structural changes, activating both proteins. Gs opens its GDP binding pocket while β2AR undergoes expansion.
- Amirhossein Mafi
- , Soo-Kyung Kim
- & William A. Goddard III
-
Article
| Open AccessAtomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates
Genetic code expansion to incorporate non-α-amino acid monomers is limited by predictability of monomer reactivities in the context of the ribosome. Now the use of metadynamics simulations of pre-attack monomers in the ribosomal peptidyl transferase centre provides insight on whether an A-site monomer is likely to be reactive.
- Zoe L. Watson
- , Isaac J. Knudson
- & Ara M. Abramyan
-
News & Views |
Illuminating enzyme design using deep learning
From humans designing machines, to machines designing biology, deep learning is turning the tables for assisted exploration of biologically active and diverse protein designs. Now, a deep-learning-based strategy has been used to design artificial enzymes that catalyse a light-emitting reaction.
- Christian Dallago
- & Kevin K. Yang
-
News & Views |
Non-complementary computation
Molecular computing programmed with complementary nucleic acid strands allows the construction of sophisticated biomolecular circuits. Now, systems with partially complementary strands have been shown to enable more compact and faster molecular circuits, and may illuminate biological processes.
- Philip Petersen
- & Grigory Tikhomirov
-
Article |
Non-complementary strand commutation as a fundamental alternative for information processing by DNA and gene regulation
The complementarity of the two strands in the DNA double helix provides a mechanism for the storage and processing of genetic information. Now, an alternative ‘strand commutation’ mechanism of data processing with DNA/RNA has been revealed based on the reversible low-affinity interactions of essentially non-complementary nucleic acids.
- Maxim P. Nikitin
-
News & Views |
Scaling up genelet circuits
DNA nanotechnology and synthetic biology both aim to expand the range of dynamic behaviours exhibited by rationally programmed biomolecules. Now, the programmability of synthetic transcriptional circuits has been improved to enable synthesis of dynamic biomolecular circuits with unmatched complexity.
- Jongmin Kim
- & Friedrich C. Simmel
-
Article |
Deep learning study of tyrosine reveals that roaming can lead to photodamage
Amino acids are one of the major building blocks of life, but the ways in which they respond to light excitation are not fully understood. Now, the photochemistry of tyrosine has been studied using physically inspired deep neural networks, leading to the observation of unconventional dynamically controlled reactivity that involves ‘roaming’ radicals that can cause photodamage.
- Julia Westermayr
- , Michael Gastegger
- & Philipp Marquetand
-
Article |
Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein
Histone H1 binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. Now it has been shown that the disordered regions of H1 retain their large-amplitude dynamics on the nucleosome, which enables a charged disordered histone chaperone to invade the H1–nucleosome complex and vastly accelerate H1 dissociation.
- Pétur O. Heidarsson
- , Davide Mercadante
- & Benjamin Schuler
-
Article
| Open AccessInteractions between nascent proteins and the ribosome surface inhibit co-translational folding
During polypeptide biosynthesis, a strong interaction can occur between a segment of an emerged, disordered nascent protein and the ribosomal surface. Now, it has been shown that competition between this ribosomal binding and the folding energetics of an immunoglobulin-like domain modulates the mechanism of co-translational folding.
- Anaïs M. E. Cassaignau
- , Tomasz Włodarski
- & John Christodoulou
-
Article |
A 68-codon genetic code to incorporate four distinct non-canonical amino acids enabled by automated orthogonal mRNA design
Non-canonical amino acids can be incorporated into proteins through translation of orthogonal mRNAs. Now, automating the design of orthogonal mRNAs—which are more selectively and efficiently translated—in combination with compact orthogonal aminoacyl-tRNA synthetase/tRNA expression systems, enables the incorporation of four distinct non-canonical monomers via a 68-codon genetic code.
- Daniel L. Dunkelmann
- , Sebastian B. Oehm
- & Jason W. Chin
-
News & Views |
Changing channels
Designing membrane proteins that function as ion channels is challenging. Now, peptides that self-assemble into water-soluble α-helical barrels have been repurposed to form ion channels in membranes by lining the interior with polar residues and the exterior with hydrophobic ones.
- Giovanna Ghirlanda
-
Article |
SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome
Simulations of the SARS-CoV-2 proteome that include over 0.1 s of aggregate data are reported. Spike opening was observed, revealing cryptic epitopes that differ between variants, explaining differential interactions with antibodies and receptors that determine pathogenicity. The cryptic pockets described provide new targets for antivirals and a wealth of mechanistic insight.
- Maxwell I. Zimmerman
- , Justin R. Porter
- & Gregory R. Bowman
-
Article |
The catalytic dwell in ATPases is not crucial for movement against applied torque
Despite the fundamental role of ATPase in catalysing ATP hydrolysis, the structural and energetic aspects of this process are not fully understood. Coarse-grained computational models have now been used to calculate the free-energy surfaces of different types of ATPases. The catalytic dwell is shown not to be crucial for movement against applied torque.
- Chen Bai
- , Mojgan Asadi
- & Arieh Warshel
-
News & Views |
Clocking growth and collapse
In biological systems, order typically emerges from out-of-equilibrium molecular processes that control both static patterns and dynamic changes. Now, the self-regulating assembly and disassembly of a synthetic system has been achieved on the micrometre scale, by coupling the growth of a DNA nanotube to a biochemical oscillator.
- Tim Liedl
-
Article |
Autonomous dynamic control of DNA nanostructure self-assembly
Nucleic acid nanotechnology offers a promising route towards the design and synthesis of reconfigurable biomolecular materials. Now, the combination of dynamic and structural DNA nanotechnology has enabled the dynamic control of the assembly and disassembly of DNA nanotubes. The process involves minimal synthetic gene systems, including an autonomous molecular oscillator.
- Leopold N. Green
- , Hari K. K. Subramanian
- & Elisa Franco
-
Review Article |
Computational advances in combating colloidal aggregation in drug discovery
Biochemical and cellular assays are often plagued by false positive readouts elicited by nuisance compounds. A significant proportion of those compounds are aggregators. This Review discusses the basis for colloidal aggregation, experimental methods for detecting aggregates and analyses recent progress in computer-based systems for detecting colloidal aggregation with particular emphasis on machine learning [In the online version of this Review originally published, the graphical abstract image was incorrectly credited to ‘Reven T.C. Wurman / Alamy Stock Photo’ this has now been corrected].
- Daniel Reker
- , Gonçalo J. L. Bernardes
- & Tiago Rodrigues
-
Article |
Chromophore twisting in the excited state of a photoswitchable fluorescent protein captured by time-resolved serial femtosecond crystallography
Providing detailed structural descriptions of the ultrafast photochemical events that occur in light-sensitive proteins is key to their understanding. Now, excited-state structures in the reversibly switchable fluorescent protein rsEGFP2 have been solved by time-resolved crystallography using an X-ray laser. These structures enabled the design of a mutant with improved photoswitching quantum yields.
- Nicolas Coquelle
- , Michel Sliwa
- & Martin Weik
-
Article |
De novo design of a hyperstable non-natural protein–ligand complex with sub-Å accuracy
The first demonstration of a protein designed entirely from first principles that binds a small-molecule cofactor in a precisely predetermined orientation has now been described. The design method utilizes a remote protein core that both anchors and predisposes a flexible binding site for the desired cofactor-binding geometry.
- Nicholas F. Polizzi
- , Yibing Wu
- & William F. DeGrado
-
Article |
Computational design of self-assembling cyclic protein homo-oligomers
A computational method to design cyclic protein homo-oligomers has been developed. Using this approach, a series of idealized repeat proteins incorporating designed interfaces that direct their assembly into complexes possessing cyclic symmetry were fabricated. 15 out of 96 oligomers that were characterized experimentally were shown to be consistent with the computational model.
- Jorge A. Fallas
- , George Ueda
- & David Baker
-
Article |
Dynamic undocking and the quasi-bound state as tools for drug discovery
Structure-based drug design has generally focused on calculating binding free energies of protein–ligand complexes. It has now been shown that structural, rather than thermodynamic, stability — specifically, the work necessary to reach a quasi-bound state in which the ligand has just broken the most important contact with the receptor — can be calculated and used as a tool in virtual screening.
- Sergio Ruiz-Carmona
- , Peter Schmidtke
- & Xavier Barril
-
Article |
High-resolution mapping of bifurcations in nonlinear biochemical circuits
Dynamic nonlinear biochemical circuits are functionally rich; however, this nonlinear nature also makes programming them delicate and painstaking. Now a droplet microfluidic platform reveals precisely the bifurcations of two canonical systems: a bistable switch and a predator–prey oscillator, exposing optimal regions and mechanistic insights that inform the design of these systems.
- A. J. Genot
- , A. Baccouche
- & Y. Rondelez
-
Thesis |
The two-week sabbatical
Could short, non-traditional sabbaticals help scientists better organize their research groups and make improvements to their laboratory's IT infrastructure? Bruce Gibb ponders this question.
- Bruce C. Gibb
Browse broader subjects
Browse narrower subjects
- Biochemical reaction networks
- Cellular signalling networks
- Classification and taxonomy
- Communication and replication
- Computational models
- Computational neuroscience
- Computational platforms and environments
- Data acquisition
- Data integration
- Data mining
- Data processing
- Data publication and archiving
- Databases
- Functional clustering
- Gene ontology
- Gene regulatory networks
- Genome informatics
- Hardware and infrastructure
- High-throughput screening
- Image processing
- Literature mining
- Machine learning
- Microarrays
- Network topology
- Phylogeny
- Power law
- Predictive medicine
- Probabilistic data networks
- Programming language
- Protein analysis
- Protein design
- Protein folding
- Protein function predictions
- Protein structure predictions
- Proteome informatics
- Quality control
- Scale invariance
- Sequence annotation
- Software
- Standards
- Statistical methods
- Virtual drug screening