Chemical descriptors encode the physicochemical and structural properties of small molecules, and they are at the core of chemoinformatics. The broad release of bioactivity data has prompted enriched ...representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Unfortunately, bioactivity descriptors are not available for most small molecules, which limits their applicability to a few thousand well characterized compounds. Here we present a collection of deep neural networks able to infer bioactivity signatures for any compound of interest, even when little or no experimental information is available for them. Our signaturizers relate to bioactivities of 25 different types (including target profiles, cellular response and clinical outcomes) and can be used as drop-in replacements for chemical descriptors in day-to-day chemoinformatics tasks. Indeed, we illustrate how inferred bioactivity signatures are useful to navigate the chemical space in a biologically relevant manner, unveiling higher-order organization in natural product collections, and to enrich mostly uncharacterized chemical libraries for activity against the drug-orphan target Snail1. Moreover, we implement a battery of signature-activity relationship (SigAR) models and show a substantial improvement in performance, with respect to chemistry-based classifiers, across a series of biophysics and physiology activity prediction benchmarks.
We present an entangling gate scheme for trapped-ion chains that achieves high-fidelity operations with excited motional states despite multiple error sources. Our approach incorporates all relevant ...motional modes and exhibits enhanced robustness against both motional heating effects and detuning errors, critical features for building robust and scalable trapped-ion quantum computers.
We show that combining ideas from the fields of quantum invariants and of
optimal control can be used to design quantum control of quantum systems
without explicit reference to quantum states. The ...scaling in numerical effort
of the resultant approach is given by commutation relations of system
operators, and it can be polynomial in the number of subsystems despite the
general quantum mechanical exponential scaling of the Hilbert space. As
explicit applications, we discuss state preparation and quantum simulation with
Hamiltonians including three-body and many-body interactions with spin chains
of up to 50 constituents, and the perspective of use for topologically
protected quantum information processing.
Noise resilience of quantum information processing is a crucial precondition to reach the fault-tolerance threshold. While resilience to many types of noise can be achieved through suitable control ...schemes, resilience to amplitude noise seems to be elusive within the common harmonic approximation for the bus mode of trapped ions. We show that weak an-harmonicities admit control schemes that achieve amplitude noise-resilience consistent with state-of-the-art experimental requirements, and that the required an-harmonicities can be achieved with current standards of micro-structured traps or even the intrinsically an-harmonic Coulomb interaction.
Optimal quantum control of continuous variable systems poses a formidable computational challenge because of the high-dimensional character of the system dynamics. The framework of quantum invariants ...can significantly reduce the complexity of such problems, but it requires the knowledge of an invariant compatible with the Hamiltonian of the system in question. We explore the potential of a Gaussian invariant that is suitable for quadratic Hamiltonians with any given number of motional degrees of freedom for quantum optimal control problems that are inspired by current challenges in ground-state-to-ground-state shuttling of trapped-ions.
Abstract
Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the ...transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster. Previous studies identified still uncharacterized, additional binding sites at the control region downstream from and slightly similar to LSP, namely sequences X and Y (Site-X and Site-Y) (Fisher et al., Cell 50, pp 247–258, 1987). Here, we explore TFAM binding at these two sites and compare them to LSP by multiple experimental and in silico methods. Our results show that TFAM binding is strongly modulated by the sequence-dependent properties of Site-X, Site-Y and LSP. The high binding versatility of Site-Y or the considerable stiffness of Site-X tune TFAM interactions. In addition, we show that increase in TFAM/DNA complex concentration induces multimerization, which at a very high concentration triggers disruption of preformed complexes. Therefore, our results suggest that mtDNA sequences induce non-uniform TFAM binding and, consequently, direct an uneven distribution of TFAM aggregation sites during the essential process of mtDNA compaction.
p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several ...diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.
There is increasing evidence for the presence of an alternative code imprinted in the genome that might contribute to gene expression regulation through an indirect reading mechanism. In mammals, ...components of this coarse-grained regulatory mechanism include chromatin structure and epigenetic signatures, where d(CpG) nucleotide steps are key players. We report a comprehensive experimental and theoretical study of d(CpG) steps that provides a detailed description of their physical characteristics and the impact of cytosine methylation on these properties. We observed that methylation changes the physical properties of d(CpG) steps, having a dramatic effect on enriched CpG segments, such as CpG islands. We demonstrate that methylation reduces the affinity of DNA to assemble into nucleosomes, and can affect nucleosome positioning around transcription start sites. Overall, our results suggest a mechanism by which the basic physical properties of the DNA fiber can explain parts of the cellular epigenetic regulatory mechanisms.
PDF
