Computational biology and bioinformatics articles within Nature Chemistry

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  • Article
    | Open Access

    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 |

    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 |

    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 Access

    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 Access

    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 |

    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 Access

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 Access

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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 |

    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

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